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No retraction, correction or concern found when last checked on Oct 25, 2026.

Prolyl isomerase Pin1: a promoter of cancer and a target for therapy

Yang Chen, Ya-ran Wu, Hong-ying Yang and 6 more

Cell Death & Disease · 2018 · Review · CC BY

doi:10.1038/s41419-018-0844-y

Abstract

Pin1 is the only known peptidyl-prolyl cis – trans isomerase (PPIase) that specifically recognizes and isomerizes the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif. The Pin1-mediated structural transformation posttranslationally regulates the biofunctions of multiple proteins. Pin1 is involved in many cellular processes, the aberrance of which lead to both degenerative and neoplastic diseases. Pin1 is highly expressed in the majority of cancers and its deficiency significantly suppresses cancer progression. According to the ground-breaking summaries by Hanahan D and Weinberg RA, the hallmarks of cancer comprise ten biological capabilities. Multiple researches illuminated that Pin1 contributes to these aberrant behaviors of cancer via promoting various cancer-driving pathways. This review summarized the detailed mechanisms of Pin1 in different cancer capabilities and certain Pin1-targeted small-molecule compounds that exhibit anticancer activities, expecting to facilitate anticancer therapies by targeting Pin1.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

Facts

Pin1 is the only known peptidyl-prolyl cis–trans isomerase (PPIase) that regulates the conformational transformation of phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif.Pin1 is highly expressed in the majority of cancers and negatively related to the clinical prognosis.Pin1 facilitates multiple cancer-driving pathways.Pin1 is a potential target for cancer therapy.

Pin1 is the only known peptidyl-prolyl cis–trans isomerase (PPIase) that regulates the conformational transformation of phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif.

Pin1 is highly expressed in the majority of cancers and negatively related to the clinical prognosis.

Pin1 facilitates multiple cancer-driving pathways.

Pin1 is a potential target for cancer therapy.

Open Questions

What are the mechanisms for the high expression of Pin1 in cancer?How does Pin1 upregulate the oncogenes and inhibit the cancer suppressors?What are the molecular mechanisms of Pin1 that lead to cancer immune escape?How does Pin1 facilitate the tumor-promoting inflammation?

What are the mechanisms for the high expression of Pin1 in cancer?

How does Pin1 upregulate the oncogenes and inhibit the cancer suppressors?

What are the molecular mechanisms of Pin1 that lead to cancer immune escape?

How does Pin1 facilitate the tumor-promoting inflammation?

Introduction

Proline (Pro)-directed Serine/Threonine (Ser/Thr) phosphorylation is a common modification of numerous signaling pathways. Many Pro-directed kinases, including mitogen-activated protein kinases and cyclin-dependent kinases (CDKs), are involved in this process–. Owing to the unique side-chain groups of proline, peptidyl-prolyl adopts an alterable cis or trans conformation. The peptidyl-prolyl cis–trans isomerases (PPIases) accelerate the structural transformation of peptidyl-prolyl to regulate the folding, subcellular location, stability, activation, and interaction of multiple proteins–. The PPIase superfamily includes cyclophilins, FK506-binding proteins (FKBPs), and parvulins (Fig. 1). Cyclophilins and FKBPs can be inhibited by the immunosuppressants cyclosporin A (CyA) and FK506/rapamycin, respectively. Pin1 belongs to parvulins and can be inhibited by juglone. It is the only known PPIase that mediates the isomerization of phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motif. Pin1 is comprised of an N-terminal WW domain and a C-terminal PPIase domain, which are connected by a flexible linker,.

The expression of Pin1 is immediately regulated by transcription factors E2F and NOTCH1. Beside, the CCAAT/enhancer binding protein-α (C/EBPα)-p30 increases Pin1 expression by recruiting E2F to the promoter of Pin1. After that, the mRNA level of Pin1 is reduced by some microRNAs (miRNAs), including the recently discovered miR-370 and miR874-3p. Moreover, the posttranslational modifications of Pin1, including phosphorylation,, sumoylation, ubiquitination, and oxidation, regulate the stability, substrate-binding ability, PPIase activity, and subcellular localization of Pin1. These processes are always aberrant in cancer that contribute to the high expression and/or overactivation of Pin1 (Fig. 2).

Pin1 is involved in multiple cellular processes, including division, differentiation, senescence, and apoptosis. Pin1 is always deficient in degenerative disorders, including Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD). In contrast, it is highly expressed in most cancers, especially in cancer stem cells (CSCs), and negatively related to the clinical prognosis–. The depletion of Pin1 significantly inhibits tumorigenesis in the mice models that are derived by mutation of p53, activation of HER2/RAS or constitutive expression of c-Myc. Additionally, many Pin1-targeted inhibitors, including all trans retinoic acid (ATRA), juglone, and KPT-6566, have showed cancer suppression ability in multiple researches (Table 1).

According to the existing research, Pin1 upregulates >50 oncogenes or proliferation-promoting factors while inhibits >20 tumor suppressors or proliferation-restraining factors, (Fig. 2). However, what are the specific mechanisms of Pin1 in different cancer capabilities? Following the ground-breaking summaries of Hanahan and Weinberg, we have a clearer recognition regarding the hallmarks of cancer. The ten major cancer capabilities are sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, resisting cell death, evading immune destruction, tumor-promoting inflammation, reprogramming of energy metabolism, and genome instability and mutation,. Mounts of researches indicated that Pin1 is an active participant of these aberrant processes (Fig. 3). In this review, we summarized the detailed mechanisms of Pin1 that contribute to these cancer capabilities and certain Pin1-targeted small-molecule compounds that exhibit anticancer activities, expecting to facilitate anticancer therapies by targeting Pin1.

Pin1 sustains the proliferative signaling

Cell proliferation is strictly regulated by the intracellular and extracellular signals,, but cancer cells utilize many pathways to sustain proliferation,. Pin1 was initially identified as a regulator of mitosis and many subsequent studies showed that it facilitates multiple proliferation-promoting pathways in cancer (Fig. 4).

Estrogen receptor α (ERα) promotes the proliferation of cancer, especially breast cancer, by regulating the expression of estrogen response element (ERE)-containing genes. Research indicated that Pin1 increases the transcriptional activity, ERE binding affinity, and inhibits the E3 ligase E6AP-induced degradation of ERα in breast cancer. The garlic extract diallyl trisulfide-treated breast cancer cells exhibit a reduced expression of Pin1 along with reduced ERα activity and cell proliferation. Besides, the high expression of Pin1 and HER2 are concurrent in most breast cancers. Pin1 activates HER2 by inhibiting its ubiquitination and destabilizing its transcriptional corepressor SMRT.

Additionally, activation of the nuclear factor (NF)-κB pathway strongly induces cancer cell proliferation. Pin1 activates the NF-κb pathway by enhancing the nuclear accumulation of RelA/p65, c-Rel, and v-Rel,. Besides, Pin1 inhibits the E3 ligase SOCS-1-mediated ubiquitination of p65. Pin1-mediated activation of the NF-κB pathway is involved in the proliferation of glioblastoma, endometrial carcinoma, acute myeloid leukemia (AML), and hepatocellular carcinoma (HCC).

Furthermore, ΔNp63, an isoform of p63 that lacks an intact N-terminal transactivation domain, is critical for tumorigenesis. Pin1 inhibits the E3 ligase WWP1-induced ubiquitination of ΔNp63 to increase the proliferation of human oral squamous cell carcinoma. Pin1 also stabilizes bromodomain-containing protein 4 (BRD4), a transactivator of multiple oncogenes, to promote the proliferation, migration, and invasion of gastric cancer. Besides, Pin1 upregulates many other proliferation-inducing factors, including β-catenin, FoxM1, XBP1, NUR77, c-Jun, and c-Myc.

Moreover, Pin1 also induces the proliferation of non-tumorous cells, such as pancreatic β cells, hepatic oval cells, and spermatogonial stem cells. The deficiency of Pin1 significantly suppresses the growth of multiple cell types, indicating that Pin1 is a potential target to treat hyperplastic diseases.

Pin1 downregulates numerous tumor suppressors

The tumor suppressors act as surveillant of multiple cellular processes to prevent cancerization and suppress cancer progression, but cancer cells utilize various mechanisms to surmount these barriers. Research indicated that Pin1 is guilty for the inactivation of numerous tumor suppressors.

When DNA is damaged, the tumor-suppressor retinoblastoma protein (pRb) directly inhibits the transcription factor E2F to arrest the cell cycle. However, pRb is usually inactivated in cancer cells due to reduced expression and/or continuously hyperphosphorylation,, which partially attribute to Pin1. The insulin-like growth factor 1-stimulated wild-type mouse embryonic fibroblasts (MEFs) exhibit hyperphosphorylated pRb and highly expressed Pin1 simultaneously, but Pin1−/− MEFs show a considerably lower level of phosphorylated pRb. Research illuminated that Pin1 promotes CDK-induced phosphorylation and inhibits PP2A-mediated dephosphorylation of pRb that subsequently activate E2F and trigger cells into S phase.

The promyelocytic leukemia protein (PML) is another powerful tumor suppressor but always mutant in cancer. Research indicated that Pin1 destabilizes PML to promote the survival and proliferation of breast cancer. Pin1 enhances the E3 adapter KLHL20-induced ubiquitination of PML to promote the proliferation and angiogenesis of prostate cancer. Besides, Pin1 also stabilizes the oncogenic fusion protein PML-RARα in AML. Suppression of Pin1 significantly inhibits the proliferation of breast cancer cells and restores the expression of PML and SMRT.

Additionally, the runt-related transcription factor 3 (RUNX3) acts as an ERα inhibitor in breast cancer. Pin1 decreases the transcriptional activity and increases the ubiquitin-dependent degradation of RUNX3. The E3 ligase FBXW7 suppresses cancer by reducing multiple oncogenes, but Pin1 inactivates FBXW7 by disrupting its dimerization and promoting its self-ubiquitination. Pin1 also downregulates other tumor suppressors, including Kruppel-like factor 10, suppressor of variegation 3-9 homolog 1, and CDK10.

Interestingly, a number of studies indicated that Pin1 increases p53-induced cell senescence and apoptosis,. However, Pin1 expression is higher in HCC cells with mutant p53 (p53M) compared to wild-type p53 (p53WT), and the deletion of Pin1 significantly reduces the proliferation of p53M HCC cells but not p53WT. More research revealed that Pin1 facilitates the p53M-induced aggressiveness of cancers,,, which contributes to a reasonable explanation for why p53 is aberrant in most cancers.

Pin1 promotes cancer invasion and metastasis

Cancer invasion and metastasis are the leading cause of death in cancer patients. Research revealed that the expression of Pin1 is much higher in the metastatic cancer compared with primary, which reduces the invasion- and metastasis-promoting function of Pin1,.

The transforming growth factor (TGF)-β pathway inhibits the proliferation but promotes the metastasis of cancer,. The SMAD proteins are major downstream adapters of TGF-β signal and extensively recognized by WW domain-containing proteins, including Pin1,. Initial research revealed that Pin1 induces the E3 ligase Smurf-2-mediated degradation of SMADs to suppress the TGF-β signal. However, the later research indicated that Pin1 promotes the TGF-β-induced metastasis of prostate cancer cells. Inhibiting the phosphorylation of SMAD3 reduces the interaction with Pin1 and remarkably suppresses the aggressiveness of breast cancer. Therefore, the function of the TGF-β pathway is complex and Pin1-mediated TGF-β pathway in cancer requires a deeper investigation.

Pin1 also increases the invasion and metastasis of cancer by activating the NOTCH pathway. In breast cancer, Pin1 facilitates the transcriptional activity of NOTCH1 by potentiating its γ-secretase-mediated cleavage. Meanwhile, NOTCH1 induces the expression of Pin1, which consequently form a positive loop to enhance cancer cell transformation. Pin1 also promotes breast CSC self-renewal and metastasis by inhibiting FBXW7-mediated degradation of NOTCH1 and NOTCH4. Besides, Pin1 activates the NOTCH3 signal by enhancing its cleavage and stabilizing its intracellular domain in T cell acute lymphoblastic leukemia (T-ALL) cell lines and mouse models. The deletion of Pin1 markedly decreases the NOTCH-induced invasion of T-ALL cells.

Moreover, PTP-PEST and FAK are two pivotal effectors of the RAS signal, which are involved in tumor metastasis. Pin1 facilitates the interaction of PTP-PEST with FAK to accelerate the Tyr397 dephosphorylation of FAK, which consequently induce the metastasis of numerous cancers,. Pin1 also promotes the epithelial–mesenchymal transition of MCF-7 cells by increasing the transcriptional activity of signal transducer and activator of transcription factor 3 (STAT3) and recruiting its transcription coactivator p300. Additionally, Pin1 promotes the invasion and metastasis of multiple cancers by activating NF-κB, p53M, β-catenin, and BRD4.

Pin1 enables the replicative immortality of cancer

After a limited number of cycles, the majority of normal cells enter a nonproliferative but viable state, which called cellular senescence. The cells that continue to divide will face a fatal crisis, which causes the death of most cells, but the minority that passes this barrier will be immortal,. The mechanisms that control the proliferative barrier include telomere shortening, DNA damage, and mitochondria damage–. The antisenescence function of Pin1 is widely revealed in vascular smooth muscle cells, cardiac progenitor cells, tendon stem/progenitor cells, fibroblasts, and various cancer cells.

In most cancer, telomerase is reactivated to maintain the telomeric DNA, but telomeric repeat-binding factors (TRFs) prevent its elongation. Research demonstrated that Pin1 elongates the telomere via promoting E3 ligase Fbx4-mediated degradation of TRF1 in multiple cancer cells. Additionally, the early mitotic inhibitor 1 (Emi1) is an inhibitor of the DNA damage-induced senescence. Pin1 promotes the proliferation and suppresses the senescence of several cancer cells by preventing the E3 ligase βTrCP-induced degradation of Emi1. Pin1 also suppresses the senescence-inducing factors pRb and PML in multiple cancers. Pin1 enhances p53-induced senescence and apoptosis; however, inhibiting Pin1 leads to senescence in p53-interfered BJ cells and overexpression of Pin1 reverses the p53 responder BTG2-induced senescence.

Furthermore, the Pin1 deficit contributes to many degenerative diseases, including AD, HD, and PD, all of which are related to aberrant neuronal senescence and apoptosis. Considering the antisenescence function, Pin1 and its substrates are potential targets to treat both degenerative diseases and cancers.

Pin1 enhances cancer-induced angiogenesis

The angiogenesis is strictly controlled in vivo. However, the rapidly expanded cancer can induce continuous angiogenesis to maintain the sustenance of nutrients and oxygen, as well as the elimination of metabolic waste and carbon dioxide. Abundant evidence illuminated that Pin1 is involved in cancer-induced angiogenesis.

The hypoxia-inducible factor 1α (HIF-1α) strongly induces angiogenesis by promoting the expression of vascular endothelial growth factor (VEGF) in the hypoxia cancer tissue. Studies indicated that the high expression of Pin1, HIF-1α, and VEGF are positively related in TAM-resistant MCF-7 (TAMR-MCF-7) cells,. Pin1 increases the stability and transcriptional activity of HIF-1α in many cancers,. PML inhibits HIF-1α-induced angiogenesis both in clear cell renal cell carcinoma and human umbilical vein endothelial cells, but Pin1 destabilizes PML in multiple cancers. HIF-1α also induces the expression of KLHL20, which cooperates with Pin1 to induce the ubiquitin-dependent degradation of PML. Besides, Pin1 facilitates the NF-κB-induced expression of VEGF in HCC. Additionally, the VEGF-promoting transcriptional factors, such as FoxM1 and β-catenin, are upregulated by Pin1 in numerous cancers.

Inhibition of Pin1 significantly reduces the cancer-induced angiogenesis. Directly suppressing the expression of Pin1 by RNAi inhibits both growth and angiogenesis of prostate cancer. The phosphoinositide-3 kinase (PI3K)/p38 signals increase the expression of Pin1 via activating E2F1. In TAMR-MCF-7 cells, the PI3K inhibitor quercetin and the E2F1 inhibitor amurensin G markedly reduced the expression of Pin1, secretion of VEGF, and angiogenesis. In conclusion, Pin1 enhances the angiogenesis of multiple cancers by promoting the expression of VEGF.

Pin1 facilitates the cell death resistance of cancer

Apoptosis is an important form of programmed cell death, which acts as a natural barrier to prevent cells from developing into cancers,. However, cancer cells can block the proapoptotic signals and activate antiapoptotic signals to make them survive in cytotoxic stress. Pin1 is a powerful “weapon” of cancer to against apoptosis.

First, Pin1 inhibits the proapoptotic factors. Outer mitochondrial membrane located BAX and BAK induce apoptosis by enhancing the release of cytochrome c. In human eosinophils (Eos), Pin1 inhibits the BAX-induced apoptosis by preventing its mitochondria translocation. Besides, the death-associated proteins DAXX and FADD are two critical responders of CD95/Fas-induced apoptosis,. The Fas signal notably increases the activity and nuclear translocation of FADD by phosphorylating its Ser194 and inhibits Pin1 by phosphorylating its Ser16. However, exogenetic expression of Pin1 maintains the cytoplasmic location of FADD by accelerating its dephosphorylation, which consequently blocks the Fas-FADD pathway. Pin1 also isomerizes DAXX to promote its ubiquitin-dependent degradation in malignant human gliomas. Additionally, DNA damage-induced apoptosis is mediated by many surveillance proteins, such as p53, PML, and pRb. However, PML and pRb are downregulated by Pin1 in numerous cancers. Pin1 enhances p53-induced apoptosis but facilitates the cancer-driving function of p53M.

Second, Pin1 upregulates the antiapoptosis factors. The B-cell lymphoma 2 (BCL-2) family proteins inhibit apoptosis via directly inactivating BAX and BAK depending on their shared BH3 domain. Research indicated that Pin1 enhances the stabilization and cell death resistance ability of BCL-2 and myeloid cell leukemia-1 (MCL-1),. Some anticancer drugs, such as sorafenib and amsacrine, induce the apoptosis of cancer cells by reversing the Pin1-mediated stability of MCL-1,. Pin1 also enhances the survival of cisplatin-treated cervical cancer cells by upregulating Wnt/β-catenin and FoxM1 pathways. In addition, Pin1 upregulates LC-3 to induce protective autophagy, which consequently increases the tamoxifen resistance of breast cancer.

Interestingly, Pin1 increases the antiapoptotic activity of Survivin in HCC, which is opposite in neuroblastoma. In addition to p53 and Survivin, Pin1 also induces cell apoptosis by activating and stabilizing the tumor-suppressor homeodomain interacting protein kinase 2, increasing the mitochondrial translocation of p66Shc, as well as inhibiting the activity of ataxia telangiectasia and rad3 related. However, all of these results were observed in non-tumorous cells.

Pin1 helps cancer cells to evade immune destruction

With further research on cancer and the immune system, the traditional concept that the immune system prevents tumor initiation and development has been questioned. Cancer cells arising from immunocompetent mice are much more aggressive than that arising from immunodeficient mice. Multiple studies demonstrated that Pin1 participates in the regulation of immune response.

The Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to initiate the immune response,. Pin1 is involved in the regulation of the TLR signals. In plasmacytoid dendritic cells, engaged TLR7/TLR9 activate interleukin (IL)-1 receptor associated kinase-1 (IRAK1) and subsequently activated IRAK1 induces the secretion of type I interferon (IFN-αβ) by activating the transcription factor IFN-regulatory factor 7 (IRF7),. IRAK1 is autophosphorylated within the activated TLR complex and then Pin1-mediated isomerization induces its liberation from the complex. Pin1-induced overactivation of the TLR-7/TLR-9/IRAK-1/IRF-7 signal contributes to the autoimmune disease systemic lupus erythematosus. In addition, IRF3 is a downstream adapter of TLR3/TLR4 signal that induces the expression of IFN-β in the antiviral response. However, Pin1 reduces the transcriptional activity and promotes ubiquitin-dependent degradation of IRF3 leading to reduced production of IFN-β in poly(I)poly(C)- or RIG-I-stimulated immune cells. Furthermore, the double-stranded RNA-induced expression of IFN-β is significantly lower and the replication of the invading virus is higher in Pin1+/+ mice compared with Pin1–/– mice. Both tripartite motif-containing 21 and PML isoform IV stabilize IRF3 and enhance IRF3-mediated production of IFN-β by disturbing the interaction of Pin1 with IRF3,. Besides, the IRF3-mediated expression of IFN-λ1 is also decreased by the exogenous expressed Pin1. In conclusion, the function of Pin1 in immune regulation is cell-type and pathogen dependent.

Pin1 is involved in the immune escape of cancer. Indoleamine-pyrrole 2,3-dioxygenase (IDO) exhausts local tryptophan to limit the function of T lymphocytes. Research indicated that the cytotoxic T lymphocyte-associated protein 4 (CTLA-4)-stimulated dendritic cells (DCs) produce IDO upon simultaneously activating the PI3K and NOTCH pathways. Pin1 increases the enzyme activity of casein kinase II to abolish the PTEN-mediated suppression of PI3K. Suppressing the NOTCH signal significantly reduces the expression of Pin1 and the CTLA-4-induced IDO production. Besides, TGF-β powerfully inhibits the proliferation and function of multiple immune cells to disorganize the host immune surveillance. In the lung, liver, and cardiac fibrosis mouse models and even in patients, Pin1 increases the expression of TGF-β by stabilizing its mRNA and protein–. It is clear that Pin1 enhances the TGF-β-induced invasion and migration of cancers, but the Pin1-mediated TGF-β signal in cancer immune escape requires a deeper investigation. In conclusion, targeting the immunoediting checkpoints is an effective strategy to treat cancer and Pin1 is a potential candidate.

Pin1 participates in the tumor-promoting inflammation

The release of necrotic cell content and microbe infection induce the inflammatory response by recruiting inflammatory cells into the local microenvironment,. Research indicated that chronic inflammation is correlative to cancer initiation and progression.

Pin1 is a regulator of inflammatory response. In human neutrophils, NADPH oxidase catalyzes the production of superoxide which subsequently generates reactive oxygen species (ROS) to annihilate ingested microbes. Pin1 promotes the formation of integrated NADPH oxidase by facilitating the membrane translocation of its cytosolic component, p47phox,. Besides, granulocyte macrophage colony-stimulating factor (GM-CSF) is essential for activation of circulating leukocytes. The 3′-untranslated region of GM-CSF mRNA is abundant in AU-rich elements (AREs) and ARE-binding protein AUF1 negatively regulates its mRNA stability. Pin1 stabilizes GM-CSF mRNA by decreasing the ARE-binding ability of AUF1 in Eos and T lymphocytes,. Inhibiting Pin1 significantly reduces the production of GM-CSF in allergen-treated rats.

The aberrant Pin1-mediated inflammation contributes to numerous diseases, including cancer. Pin1 enhances the IL-22-induced proliferation and survival of breast cancer cells by activating mitogen-activated extracellular signal-regulated kinases, c-Jun, and STAT3. Pin1 also increases the nuclear translocation of IRAK-M in DCs to enhance the IL-33-induced allergic airway inflammation. Besides, Pin1 is correlated in other inflammatory diseases, including rheumatoid arthritis, periodontitis, diabetes-induced atherosclerosis, nonalcoholic steatohepatitis, and primary biliary cholangitis.

However, research indicates that Pin1 also stabilizes and activates some anti-inflammatory proteins, such as NUR77 and glucocorticoid receptor. Similar to the immune regulation, Pin1 probability plays a dual role in inflammation regulation, but the cancer-promoting function of Pin1 is much more clarified.

Pin1 regulates the metabolic reprogramming of cancer

The metabolic pattern of glucose in mammalian cells is dependent on the oxygen environment. In aerobic conditions, the common intermediate pyruvate is mainly transferred to the mitochondria and efficiently produces massive ATP through oxidative phosphorylation, while in anaerobic conditions, pyruvate rapidly produces small amounts of ATP via glycolysis in the cytoplasm. The majority of normal cells are fueled by more efficient oxidative phosphorylation except for some special conditions, such as muscle cells in high-intensity exercise. However, the major metabolic pattern of cancer cells is glycolysis even in aerobic conditions, which called “aerobic glycolysis” or “Warburg effect” after its discoverer, Otto Warburg. The “Warburg effect” is beneficial for cancer progression by supplying intermediates for rapid biosynthesis and avoiding cytostatic controls that are induced by activated oncogenes and/or mutant cancer suppressors,. The mechanisms that result in “Warburg effect” include increased glucose import, aberrant hypoxia response system, and the incapacitation of oxidative phosphorylation. They are correlated with many aberrant signals, including PI3K/Akt/mammalian target of rapamycin, Wnt/β-catenin, HIF-1α, and non-coding RNAs, all of which finally regulate the expression and/or activation of metabolism-associated proteins.

Research indicates that Pin1 is a crucial regulator of the “Warburg effect” (Fig. 5). Pin1 increases the nuclear localization of the phosphorylated pyruvate kinase isozyme M2 (PKM2). The nuclear translocated PKM2 phosphorylates histone H3-T11 leading to the H3-K9 acetylation of target genes. Meanwhile, it also acts as a co-activator of β-catenin to increase the expression of CCDN1 and c-Myc. Subsequently, c-Myc induces the expression of glucose transporter 1 and lactate dehydrogenase A to promote the “Warburg effect”,. In addition, pyruvate dehydrogenase kinase 1 (PDHK1) suppresses the tricarboxylic cycle by phosphorylating and inactivating the pyruvate dehydrogenase (PDH) complex. Pin1 increases the mitochondria translocation of PGK1 where it activates PDHK1 to facilitate the PDH-inhibited activity of PDHK1. Moreover, Pin1 upregulates many other metabolic regulators directly, such as β-catenin, HIF-1α, and c-Myc. Targeting the metabolic reprogramming process is effective to suppress cancer progression, and these studies revealed that Pin1 is a potential candidate to reverse these dysregulations.

Pin1 contributes to the genome instability and mutations of cancer

Cytotoxic factors, such as ionizing radiation and DNA topoisomerase II poisons, induce DNA double-strand breaks (DSBs) to trigger cellular senescence and apoptosis. It is effective to suppress cancer by bringing in a mass of DNA damage, but most cancer is insensitive to genome instability and mutations. Pin1 not only suppresses the DAN damage-induced senescence and apoptosis but also contributes the genome instability in cancers.

The mechanisms of DSBs repair include error-free homologous recombination (HR) and fallible nonhomologous end-joining (NHEJ). CtIP facilitates HR by promoting DNA-end resection. However, Pin1 promotes the ubiquitin-dependent degradation of CtIP to attenuate HR and increase NHEJ, which consequently increase genome instability. Pin1 also interacts with the DSB repair regulators 53BP1 and BRCA1, but there is no further study on them. Besides, it is a promising direction that Pin1 modifies DSB repair through regulating the CDK-mediated DNA-end resection. Meanwhile, rapid proliferation leads to replication-associated DNA damage. Whether the Pin1-promoted proliferation induces DNA damage is also worth of deeper research.

The aberrant mitotic process also contributes to genome instability. Separase promotes sister chromatid paired segregation by cleaving ring-shaped cohesin. Research indicated that the full function of separase requires the Pin1-mediated isomerization at its pSer1126-Pro motif. The centrosome protein 55 kDa (Cep55) is crucial for the formation of midbodies in cytokinesis. Pin1 increases the midbody translocation of Cep55 by facilitating its polo-like kinase 1-mediated phosphorylation at Ser436. Pin1 is also involved in the SEPT9-mediated final separation of daughter cells. Moreover, the overexpression of Pin1 promotes an abnormal centrosome duplication and chromosome instability in breast cancer. Human papillomavirus (HPV) infection also induces genome instability and enhances the malignant phenotype of cervical cancers by promoting aberrant centrosome synthesis. Research indicates that HPV-infected cervical lesions exhibit an elevated level of Pin1, but the relationship of HPV-induced Pin1 and genome instability in cervical cancer requires a deeper investigation.

Targeting Pin1 is effective to suppress cancer

Targeting a single pathway to treat cancer is challenging because multiple aberrant pathways are involved in cancer progression,. Moreover, almost all of the current therapies are ineffective to treat CSCs. Therefore, a strategy that simultaneously targets multiple cancer-driving pathways is urgently required. In cancers, Pin1 promotes and suppresses numerous oncogenes and tumor suppressors, respectively. Multiple studies demonstrated that inhibition of Pin1 is effective to suppress the progression of cancers. Aurora kinase A, ribosomal S6 kinase 2 and protein kinase A abolish the substrate interaction ability of Pin1 by phosphorylating its Ser16 residue in the WW domain. The death-associated protein kinase 1 inactivates Pin1 by phosphorylating Ser71 in the catalytic core of Pin1 that consequently inhibits the centrosome amplification of breast cancer cells but aggravates neurodegeneration. Pin1-targeted microRNAs (miRNAs), including miR-200b, miR-200c, miR296-5p, miR-370, and miR874-3p, inhibit human cancer progression via directly decreasing the mRNA level of Pin1. However, Pin1 can suppress the miRNA biogenesis by inhibiting exportin-5 (XPO5). In addition, researchers have discovered and synthesized many Pin1-targeted small-molecule compounds that exhibit anticancer activity (Table 1). ATRA, a currently used target drug for acute promyelocytic leukemia (APL), mechanically combines with the substrate-binding site of Pin1 to inhibit its activation in APL and breast cancer cells. Yang et al. designed a novel slow-releasing, non-toxic, biodegradable, and biocompatible ATRA formulation. Their work showed that this novel formulation exhibits long-term inhibition of Pin1 and is more efficient than the traditional ATRA to suppress HCC cell growth. Juglone, a compound extracted from walnut tree, and its derivative buparvaquone both inhibit Pin1 by covalently modifying its catalytic core,. Juglone is effective to suppress multiple cancer cells and universally used in Pin1 research. Cis-locked alkene peptidomimetics inhibit Pin1 by simulating a substrate of Pin1 and exhibit antiproliferation activities in an ovarian cancer cell line. Imazamethabenz, an imidazoline ketone herbicide, inhibits migration and invasion and induces apoptosis in breast cancer cells via directly combining with Pin1. The Pin1 inhibitor API-1 suppresses HCC development by restoring Pin1-inhibited miRNA biogenesis. Recently, a novel Pin1 inhibitor, KPT-6566, inhibits the PPIase activity and induces the degradation of Pin1 by covalently interacting with its catalytic core. Moreover, inhibiting Pin1 sensitizes many cancer cells to chemotherapy, including HCC to sorafenib, breast cancer to trastuzumab, rapamycin, Taxol and 5-fluorouracil, colon cancer to Taxol, and AML to retinoic acid. Increasing evidence showed that Pin1 is a potential target for cancer therapy. However, the majority of the existing inhibitors lack the required specificity, efficacy, and safety in clinical application.

Conclusions

The diversity and complexity of cancers are always challenging the treatment. Fortunately, after decades of research, we are uncovering the secret of cancer. Hanahan and Weinberg summarized the common hallmarks of cancer cells, which lets us recognize cancers more clearly. Currently, targeted therapies have applied to the treatment of multiple cancers, which have a higher efficacy and lower side effects than traditional therapies. However, the “smart” cancer cells, especially the CSCs, utilize multiple mechanisms to avoid being eradicated. Therefore, therapies that target common aberrant pathways to block the escape of tumor cells are urgently warranted. Pro-directed phosphorylation is an extensive modification of numerous pathways, which regulate multiple basic cellular processes, including proliferation, differentiation, metabolism, and death. Pin1 is the only known PPIase that mediates the cis–trans isomerization of pSer/Thr-Pro bond, which highlights its significance in the regulation of Pro-directed phosphorylation.

Pin1 is highly expressed in most cancers, especially CSCs. According to the existing discovery, some regulation loops, including at least Pin1/NOTCH/Pin1 axis, Pin1/pRb/E2F/Pin1 axis,,, and Pin1/XPO5/miRNAs/Pin1 axis,, contribute to the high expression of Pin1. Pin1 is involved in almost every cancer biocapability, suggesting that it is a potential common therapeutic target. There are many Pin1-targeted inhibitors, including the novel structure-based designed compounds, natural extracts, and their derivatives, that exhibit anticancer activity in in vitro, animal models and even in certain patients. Hence, the mechanisms of Pin1-induced cancer progression and targeting Pin1 for cancer therapy are worthy of further investigation. When matured, the extensive clinical applications would benefit many cancer patients.

References 241

  1. 1.

    Pearson G, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev. 2001;22:153-183.

    Not in our library10.1210/edrv.22.2.0428

  2. 2.

    Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell Dev. Biol. 1997;13:261-291.

    Not in our library10.1146/annurev.cellbio.13.1.261

  3. 3.

    Lu KP, Liou YC, Zhou XZ. Pinning down proline-directed phosphorylation signaling. Trends Cell Biol. 2002;12:164-172.

    Not in our library10.1016/s0962-8924(02)02253-5

  4. 4.

    Reimer U, et al. Side-chain effects on peptidyl-prolyl cis/trans isomerisation. J. Mol. Biol. 1998;279:449-460.

    Not in our library10.1006/jmbi.1998.1770

  5. 5.

    Lu KP, Finn G, Lee TH, Nicholson LK. Prolyl cis-trans isomerization as a molecular timer. Nat. Chem. Biol. 2007;3:619-629.

    Not in our library10.1038/nchembio.2007.35

  6. 6.

    Takahashi K, Uchida C, Shin RW, Shimazaki K, Uchida T. Prolyl isomerase, Pin1: new findings of post-translational modifications and physiological substrates in cancer, asthma and Alzheimer’s disease. Cell. Mol. Life Sci. 2008;65:359-375.

    Not in our library10.1007/s00018-007-7270-0

  7. 7.

    Gothel SF, Marahiel MA. Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell. Mol. Life Sci. 1999;55:423-436.

    Not in our library10.1007/s000180050299

  8. 8.

    Zhou XZ, Lu KP. The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target. Nat. Rev. Cancer. 2016;16:463-478.

    Not in our library10.1038/nrc.2016.49

  9. 9.

    Hennig L, et al. Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone. Biochemistry. 1998;37:5953-5960.

    Not in our library10.1021/bi973162p

  10. 10.

    Lu KP, Zhou XZ. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat. Rev. Mol. Cell Biol. 2007;8:904-916.

    Not in our library10.1038/nrm2261

  11. 11.

    Verdecia MA, Bowman ME, Lu KP, Hunter T, Noel JP. Structural basis for phosphoserine-proline recognition by group IV WW domains. Nat. Struct. Biol. 2000;7:639-643.

    Not in our library10.1038/77929

  12. 12.

    Matena A, Rehic E, Hönig D, Kamba B, Bayer P. Structure and function of the human parvulins Pin1 and Par14/17. Biol. Chem. 2018;399:101-125.

    Not in our library10.1515/hsz-2017-0137

  13. 13.

    Ryo A, et al. PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. Mol. Cell. Biol. 2002;22:5281-5295.

    Not in our library10.1128/mcb.22.15.5281-5295.2002

  14. 14.

    Rustighi A, et al. The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat. Cell Biol. 2009;11:133-142.

    Not in our library10.1038/ncb1822

  15. 15.

    Pulikkan JA, et al. Elevated PIN1 expression by C/EBPalpha-p30 blocks C/EBPalpha-induced granulocytic differentiation through c-Jun in AML. Leukemia. 2010;24:914-923.

    Not in our library10.1038/leu.2010.37

  16. 16.

    Chen M, et al. Downregulation of microRNA-370 in esophageal squamous-cell carcinoma is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1. Gene. 2018;661:68-77.

    Not in our library10.1016/j.gene.2018.03.090

  17. 17.

    Leong K, et al. miR-874-3p is down-regulated in hepatocellular carcinoma and negatively regulates PIN1 expression. Oncotarget. 2017;8:11343-11355.

    Not in our library10.18632/oncotarget.14526

  18. 18.

    Lee TH, et al. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol. Cell. 2011;42:147-159.

    Not in our library10.1016/j.molcel.2011.03.005

  19. 19.

    Lu PJ, Zhou XZ, Liou YC, Noel JP, Lu KP. Critical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function. J. Biol. Chem. 2002;277:2381-2384.

    Not in our library10.1074/jbc.c100228200

  20. 20.

    Chen CH, et al. SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function. Cancer Res. 2013;73:3951-3962.

    Not in our library10.1158/0008-5472.can-12-4360

  21. 21.

    Eckerdt F, et al. Polo-like kinase 1-mediated phosphorylation stabilizes Pin1 by inhibiting its ubiquitination in human cells. J. Biol. Chem. 2005;280:36575-36583.

    Not in our library10.1074/jbc.m504548200

  22. 22.

    Chen CH, et al. Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer’s disease. Neurobiol. Dis. 2015;76:13-23.

    Not in our library10.1016/j.nbd.2014.12.027

  23. 23.

    Yaffe MB, et al. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science. 1997;278:1957-1960.

    Not in our library10.1126/science.278.5345.1957

  24. 24.

    Hsu T, McRackan D, Vincent TS, Gert de Couet H. Drosophila Pin1 prolyl isomerase Dodo is a MAP kinase signal responder during oogenesis. Nat. Cell Biol. 2001;3:538-543.

    Not in our library10.1038/35078508

  25. 25.

    Toko H, et al. Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells. J. Biol. Chem. 2014;289:5348-5356.

    Not in our library10.1074/jbc.m113.526442

  26. 26.

    Pinton P, et al. Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science. 2007;315:659-663.

    Not in our library10.1126/science.1135380

  27. 27.

    Ryo A, et al. Prolyl-isomerase Pin1 accumulates in lewy bodies of parkinson disease and facilitates formation of alpha-synuclein inclusions. J. Biol. Chem. 2006;281:4117-4125.

    Not in our library10.1074/jbc.m507026200

  28. 28.

    Pastorino L, et al. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature. 2006;440:528-534.

    Not in our library10.1038/nature04543

  29. 29.
    PIN1 Modulates Huntingtin Levels and Aggregate Accumulation: An In vitro Model · 2017
    Not checked
  30. 30.

    Lu Z, Hunter T. Prolyl isomerase Pin1 in cancer. Cell Res. 2014;24:1033-1049.

    Not in our library10.1038/cr.2014.109

  31. 31.

    Luo ML, et al. Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res. 2014;74:3603-3616.

    Not in our library10.1158/0008-5472.can-13-2785

  32. 32.
    Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast · 2013
    Corrected
  33. 33.

    Girardini JE, et al. A Pin1/mutant p53 axis promotes aggressiveness in breast cancer. Cancer Cell. 2011;20:79-91.

    Not in our library10.1016/j.ccr.2011.06.004

  34. 34.

    Wulf G, Garg P, Liou YC, Iglehart D, Lu KP. Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J. 2004;23:3397-3407.

    Not in our library10.1038/sj.emboj.7600323

  35. 35.

    D’Artista L, et al. Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc. Oncotarget. 2016;7:21786-21798.

    Not in our library10.18632/oncotarget.7846

  36. 36.

    Wei S, et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat. Med. 2015;21:457-466.

    Not in our library10.1038/nm.3839

  37. 37.

    Kim MR, et al. Enhancement of vascular endothelial growth factor-mediated angiogenesis in tamoxifen-resistant breast cancer cells: role of Pin1 overexpression. Mol. Cancer Ther. 2009;8:2163-2171.

    Not in our library10.1158/1535-7163.mct-08-1061

  38. 38.
    A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action · 2017
    No notice
  39. 39.

    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.

    Not in our library10.1016/s0092-8674(00)81683-9

  40. 40.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.

    Not in our library10.1016/j.cell.2011.02.013

  41. 41.

    Wang Y, et al. N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications. Nat. Neurosci. 2018;21:195-206.

    Not in our library10.1038/s41593-017-0057-1

  42. 42.

    Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA. Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes. 2011;60:827-837.

    Not in our library10.2337/db10-1194

  43. 43.

    Espana-Agusti J, Warren A, Chew SK, Adams DJ, Matakidou A. Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis. Nat. Commun. 2017;8:2026.

    Not in our library10.1038/s41467-017-02245-1

  44. 44.

    Raleigh DR, et al. Hedgehog signaling drives medulloblastoma growth via CDK6. J. Clin. Invest. 2018;128:120-124.

    Not in our library10.1172/jci92710

  45. 45.

    Lu KP, Hanes SD, Hunter T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature. 1996;380:544-547.

    Not in our library10.1038/380544a0

  46. 46.

    Lin CH, et al. Landscape of Pin1 in the cell cycle. Exp. Biol. Med. (Maywood). 2015;240:403-408.

    Not in our library10.1177/1535370215570829

  47. 47.

    Anderson E. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res. 2002;4:197-201.

    Not in our library10.1186/bcr452

  48. 48.

    Rajbhandari P, et al. Regulation of estrogen receptor α N-terminus conformation and function by peptidyl prolyl isomerase Pin1. Mol. Cell. Biol. 2012;32:445-457.

    Not in our library10.1128/mcb.06073-11

  49. 49.

    Rajbhandari P, Ozers MS, Solodin NM, Warren CL, Alarid ET. Peptidylprolyl isomerase Pin1 directly enhances the DNA binding functions of estrogen receptor α. J. Biol. Chem. 2015;290:13749-13762.

    Not in our library10.1074/jbc.m114.621698

  50. 50.

    Rajbhandari P, et al. Pin1 modulates ERα levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation. Oncogene. 2014;33:1438-1447.

    Not in our library10.1038/onc.2013.78

  51. 51.

    Hahm ER, Singh SV. Diallyl trisulfide inhibits estrogen receptor-α activity in human breast cancer cells. Breast Cancer Res. Treat. 2014;144:47-57.

    Not in our library10.1007/s10549-014-2841-x

  52. 52.

    Lam PB, et al. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability. Mol. Cancer. 2008;7:91.

    Not in our library10.1186/1476-4598-7-91

  53. 53.

    Stanya KJ, Liu Y, Means AR, Kao HY. Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT. J. Cell. Biol. 2008;183:49-61.

    Not in our library10.1083/jcb.200806172

  54. 54.

    Ryo A, et al. Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol. Cell. 2003;12:1413-1426.

    Not in our library10.1016/s1097-2765(03)00490-8

  55. 55.

    Fan G, et al. Peptidyl-prolyl isomerase Pin1 markedly enhances the oncogenic activity of the rel proteins in the nuclear factor-kappaB family. Cancer Res. 2009;69:4589-4597.

    Not in our library10.1158/0008-5472.can-08-4117

  56. 56.

    Atkinson GP, et al. The prolyl isomerase Pin1 regulates the NF-kappaB signaling pathway and interleukin-8 expression in glioblastoma. Oncogene. 2009;28:3735-3745.

    Not in our library10.1038/onc.2009.232

  57. 57.

    Saegusa M, Hashimura M, Kuwata T. Pin1 acts as a modulator of cell proliferation through alteration in NF-κB but not β-catenin/TCF4 signalling in a subset of endometrial carcinoma cells. J. Pathol. 2010;222:410-420.

    Not in our library10.1002/path.2773

  58. 58.

    Chen JY, et al. The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells. Sci. Rep. 2016;6:32428.

    Not in our library10.1038/srep32428

  59. 59.

    Shinoda K, et al. Pin1 facilitates NF-κB activation and promotes tumour progression in human hepatocellular carcinoma. Br. J. Cancer. 2015;113:1323-1331.

    Not in our library10.1038/bjc.2015.272

  60. 60.

    Murray-Zmijewski F, Lane DP, Bourdon JC. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ. 2006;13:962-972.

    Not in our library10.1038/sj.cdd.4401914

  61. 61.

    Li C, et al. Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation. Cell Death Dis. 2013;4:e943.

    Not in our library10.1038/cddis.2013.468

  62. 62.

    Hu X, et al. Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4. Oncogene. 2017;36:5177-5188.

    Not in our library10.1038/onc.2017.137

  63. 63.

    Zhu Z, et al. Pin1 promotes prostate cancer cell proliferation and migration through activation of Wnt/β-catenin signaling. Clin. Transl. Oncol. 2016;18:792-797.

    Not in our library10.1007/s12094-015-1431-7

  64. 64.

    Kruiswijk F, et al. Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling. Oncogene. 2016;35:2166-2177.

    Not in our library10.1038/onc.2015.282

  65. 65.

    Chae U, et al. Critical role of XBP1 in cancer signalling is regulated by PIN1. Biochem. J. 2016;473:2603-2610.

    Not in our library10.1042/bcj20160482

  66. 66.

    Chen HZ, et al. Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis. Oncogene. 2012;31:2876-2887.

    Not in our library10.1038/onc.2011.463

  67. 67.

    Csizmok V, et al. Multivalent interactions with Fbw7 and Pin1 facilitate recognition of c-Jun by the SCFFbw7 ubiquitin ligase. Structure. 2018;26:28-39.

    Not in our library10.1016/j.str.2017.11.003

  68. 68.

    Helander S, et al. Pre-anchoring of Pin1 to unphosphorylated c-Myc in a fuzzy complex regulates c-Myc activity. Structure. 2015;23:2267-2279.

    Not in our library10.1016/j.str.2015.10.010

  69. 69.

    Nakatsu Y, et al. The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion. J. Biol. Chem. 2017;292:11886-11895.

    Not in our library10.1074/jbc.m117.780726

  70. 70.

    Risal P, Shrestha N, Chand L, Sylvester KG, Jeong YJ. Involvement of prolyl isomerase PIN1 in the cell cycle progression and proliferation of hepatic oval cells. Pathol. Res. Pract. 2017;213:373-380.

    Not in our library10.1016/j.prp.2017.01.005

  71. 71.

    Kanatsu-Shinohara M, Onoyama I, Nakayama KI, Shinohara T. Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal. Proc. Natl. Acad. Sci. USA. 2014;111:8826-8831.

    Not in our library10.1073/pnas.1401837111

  72. 72.

    Avni D, et al. Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage. Mol. Cell. 2003;12:735-746.

    Not in our library10.1016/s1097-2765(03)00355-1

  73. 73.

    Valenciaga A, et al. Reduced retinoblastoma protein expression is associated with decreased patient survival in medullary thyroid cancer. Thyroid. 2017;27:1523-1533.

    Not in our library10.1089/thy.2017.0113

  74. 74.

    Ying L, et al. Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation. Cancer Res. 2005;65:9132-9136.

    Not in our library10.1158/0008-5472.can-05-1358

  75. 75.

    You H, et al. IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry. J. Cell. Biochem. 2002;84:211-216.

    Not in our library10.1002/jcb.10037

  76. 76.

    Rizzolio F, et al. Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1. Cell Death Differ. 2012;19:1152-1161.

    Not in our library10.1038/cdd.2011.202

  77. 77.

    Tong Y, et al. Pin1 inhibits PP2A-mediated Rb dephosphorylation in regulation of cell cycle and S-phase DNA damage. Cell Death Dis. 2015;6:e1640.

    Not in our library10.1038/cddis.2015.3

  78. 78.

    Lim JH, Liu Y, Reineke E, Kao HY. Mitogen-activated protein kinase extracellular signal-regulated kinase 2 phosphorylates and promotes Pin1 protein-dependent promyelocytic leukemia protein turnover. J. Biol. Chem. 2011;286:44403-44411.

    Not in our library10.1074/jbc.m111.289512

  79. 79.

    Yuan WC, et al. A Cullin3-KLHL20 ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell. 2011;20:214-228.

    Not in our library10.1016/j.ccr.2011.07.008

  80. 80.

    Liu T, Liu Y, Kao HY, Pei D. Membrane permeable cyclic peptidyl inhibitors against human peptidylprolyl isomerase Pin1. J. Med. Chem. 2010;53:2494-2501.

    Not in our library10.1021/jm901778v

  81. 81.

    Gianni M, et al. Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of RARalpha and PML-RARalpha. Cancer Res. 2009;69:1016-1026.

    Not in our library10.1158/0008-5472.can-08-2603

  82. 82.

    Huang B, et al. RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α. Oncogene. 2012;31:527-534.

    Not in our library10.1038/onc.2011.252

  83. 83.

    Nicole Tsang YH, et al. Prolyl isomerase Pin1 downregulates tumor suppressor RUNX3 in breast cancer. Oncogene. 2013;32:1488-1496.

    Not in our library10.1038/onc.2012.178

  84. 84.

    Min SH, et al. Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol. Cell. 2012;46:771-783.

    Not in our library10.1016/j.molcel.2012.04.012

  85. 85.

    Hwang YC, et al. Destabilization of KLF10, a tumor suppressor, relies on thr93 phosphorylation and isomerase association. Biochim. Biophys. Acta. 2013;1833:3035-3045.

    Not in our library10.1016/j.bbamcr.2013.08.010

  86. 86.

    Khanal P, et al. Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer. FASEB J. 2013;27:4606-4618.

    Not in our library10.1096/fj.13-236851

  87. 87.

    Khanal P, et al. Proyl isomerase Pin1 facilitates ubiquitin-mediated degradation of cyclin-dependent kinase 10 to induce tamoxifen resistance in breast cancer cells. Oncogene. 2012;31:3845-3856.

    Not in our library10.1038/onc.2011.548

  88. 88.

    Sorrentino G, et al. The prolyl-isomerase Pin1 activates the mitochondrial death program of p53. Cell Death Differ. 2013;20:198-p208.

    Not in our library10.1038/cdd.2012.112

  89. 89.

    Follis AV, et al. Pin1-induced proline isomerization in cytosolic p53 mediates BAX activation and apoptosis. Mol. Cell. 2015;59:677-684.

    Not in our library10.1016/j.molcel.2015.06.029

  90. 90.

    Bae JS, et al. PIN1 in hepatocellular carcinoma is associated with TP53 gene status. Oncol. Rep. 2016;36:2405-2411.

    Not in our library10.3892/or.2016.5001

  91. 91.

    Liao P, et al. Mutant p53 gains its function via c-Myc activation upon CDK4 phosphorylation at serine 249 and consequent PIN1 binding. Mol. Cell. 2017;68:1134-1146.

    Not in our library10.1016/j.molcel.2017.11.006

  92. 92.

    Hu H, Wulf GM. The amplifier effect: how Pin1 empowers mutant p53. Breast Cancer Res. 2011;13:315.

    Not in our library10.1186/bcr2941

  93. 93.

    Chen SY, et al. Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction. Mol. Cell. Biol. 2006;26:929-939.

    Not in our library10.1128/mcb.26.3.929-939.2006

  94. 94.

    He J, et al. Overexpression of Pin1 in non-small cell lung cancer (NSCLC) and its correlation with lymph node metastases. Lung Cancer. 2007;56:51-58.

    Not in our library10.1016/j.lungcan.2006.11.024

  95. 95.

    Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat. Genet. 2001;29:117-129.

    Not in our library10.1038/ng1001-117

  96. 96.

    Massagué J. TGFbeta in cancer. Cell. 2008;134:215-230.

    Not in our library10.1016/j.cell.2008.07.001

  97. 97.

    Shen ZJ, et al. Pin1 protein regulates Smad protein signaling and pulmonary fibrosis. J. Biol. Chem. 2012;287:23294-23305.

    Not in our library10.1074/jbc.m111.313684

  98. 98.

    Aragón E, et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 2011;25:1275-1288.

    Not in our library10.1101/gad.2060811

  99. 99.

    Nakano A, et al. Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins. J. Biol. Chem. 2009;284:6109-6115.

    Not in our library10.1074/jbc.m804659200

  100. 100.

    Matsuura I, et al. Pin1 promotes transforming growth factor-beta-induced migration and invasion. J. Biol. Chem. 2010;285:1754-1764.

    Not in our library10.1074/jbc.m109.063826

  101. 101.

    Thomas AL, et al. Inhibition of CDK-mediated Smad3 phosphorylation reduces the Pin1-Smad3 interaction and aggressiveness of triple negative breast cancer cells. Cell Cycle. 2017;16:1453-1464.

    Not in our library10.1080/15384101.2017.1338988

  102. 102.

    Franciosa G, et al. Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression. Oncogene. 2016;35:4741-4751.

    Not in our library10.1038/onc.2016.5

  103. 103.

    Lee KJ, et al. CD99-derived agonist ligands inhibit fibronectin-induced activation of β1 integrin through the protein kinase A/SHP2/extracellular signal-regulated kinase/PTPN12/focal adhesion kinase signaling pathway. Mol. Cell. Biol. 2017;37:e00675-16.

    Not in our library10.1128/mcb.00675-16

  104. 104.

    Zheng Y, et al. FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Mol. Cell. 2009;35:11-25.

    Not in our library10.1016/j.molcel.2009.06.013

  105. 105.

    Zheng Y, et al. Ras-induced and extracellular signal-regulated kinase 1 and 2 phosphorylation-dependent isomerization of protein tyrosine phosphatase (PTP)-PEST by PIN1 promotes FAK dephosphorylation by PTP-PEST. Mol. Cell. Biol. 2011;31:4258-4269.

    Not in our library10.1128/mcb.05547-11

  106. 106.

    Lufei C, Koh TH, Uchida T, Cao X. Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity. Oncogene. 2007;26:7656-7664.

    Not in our library10.1038/sj.onc.1210567

  107. 107.

    Wang J, et al. FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling. Oncogene. 2012;31:4798-4802.

    Not in our library10.1038/onc.2011.635

  108. 108.

    Muller PA, et al. Mutant p53 drives invasion by promoting integrin recycling. Cell. 2009;139:1327-1341.

    Not in our library10.1016/j.cell.2009.11.026

  109. 109.

    Frey N, Venturelli S, Zender L, Bitzer M. Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat. Rev. Gastroenterol. Hepatol. 2018;15:81-95.

    Not in our library10.1038/nrgastro.2017.146

  110. 110.

    Birch J, Barnes PJ, Passos JF. Mitochondria, telomeres and cell senescence: Implications for lung ageing and disease. Pharmacol. Ther. 2018;183:34-49.

    Not in our library10.1016/j.pharmthera.2017.10.005

  111. 111.

    He S, Sharpless NE. Senescence in health and disease. Cell. 2017;169:1000-1011.

    Not in our library10.1016/j.cell.2017.05.015

  112. 112.

    Lv L, et al. Downregulation of Pin1 in human atherosclerosis and its association with vascular smooth muscle cell senescence. J. Vasc. Surg. 2017;S0741-5214:32213-32219.

    Not in our library10.1016/j.jvs.2017.09.006

  113. 113.

    Chen L, et al. The role of Pin1 protein in aging of human tendon stem/progenitor cells. Biochem. Biophys. Res. Commun. 2015;464:487-492.

    Not in our library10.1016/j.bbrc.2015.06.163

  114. 114.

    Wheaton K, Muir J, Ma W, Benchimol S. BTG2 antagonizes Pin1 in response to mitogens and telomere disruption during replicative senescence. Aging Cell. 2010;9:747-760.

    Not in our library10.1111/j.1474-9726.2010.00601.x

  115. 115.

    van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature. 1997;385:740-743.

    Not in our library10.1038/385740a0

  116. 116.

    Lee TH, et al. Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance. Nat. Cell Biol. 2009;11:97-105.

    Not in our library10.1038/ncb1818

  117. 117.

    Hsu JY, Reimann JD, Sørensen CS, Lukas J, Jackson PK. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat. Cell Biol. 2002;4:358-366.

    Not in our library10.1038/ncb785

  118. 118.

    Bernis C, et al. Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCF(betatrcp). EMBO Rep. 2007;8:91-98.

    Not in our library10.1038/sj.embor.7400853

  119. 119.

    Cheng CW, Leong KW, Tse E. Understanding the role of PIN1 in hepatocellular carcinoma. World J. Gastroenterol. 2016;22:9921-9932.

    Not in our library10.3748/wjg.v22.i45.9921

  120. 120.

    Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med. 2003;9:677-684.

    Not in our library10.1038/nm0603-677

  121. 121.

    Lee KY, et al. PI3-kinase/p38 kinase-dependent E2F1 activation is critical for Pin1 induction in tamoxifen-resistant breast cancer cells. Mol. Cells. 2011;32:107-111.

    Not in our library10.1007/s10059-011-0074-y

  122. 122.

    Oh SJ, et al. Inhibition of angiogenesis by quercetin in tamoxifen-resistant breast cancer cells. Food Chem. Toxicol. 2010;48:3227-3234.

    Not in our library10.1016/j.fct.2010.08.028

  123. 123.

    Han HJ, et al. Peptidyl prolyl isomerase PIN1 directly binds to and stabilizes hypoxia-inducible factor-1α. PLoS ONE. 2016;11:e147038.

    Not in our library10.1371/journal.pone.0147038

  124. 124.

    Jalouli M, et al. The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity. Cell. Signal. 2014;26:1649-1656.

    Not in our library10.1016/j.cellsig.2014.04.005

  125. 125.

    Lin YC, et al. SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling. Cancer Res. 2014;74:6935-6946.

    Not in our library10.1158/0008-5472.can-14-1330

  126. 126.

    Hsu KS, et al. Translational control of PML contributes to TNFα-induced apoptosis of MCF7 breast cancer cells and decreased angiogenesis in HUVECs. Cell Death Differ. 2016;23:469-483.

    Not in our library10.1038/cdd.2015.114

  127. 127.

    Wang Z, Banerjee S, Kong D, Li Y, Sarkar FH. Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. Cancer Res. 2007;67:8293-8300.

    Not in our library10.1158/0008-5472.can-07-1265

  128. 128.

    Jiang L, et al. Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis. Circ. Res. 2015;117:364-375.

    Not in our library10.1161/circresaha.115.306829

  129. 129.

    Ryo A, et al. Stable suppression of tumorigenicity by Pin1-targeted RNA interference in prostate cancer. Clin. Cancer Res. 2005;11:7523-7531.

    Not in our library10.1158/1078-0432.ccr-05-0457

  130. 130.

    Kim JA, et al. Amurensin G inhibits angiogenesis and tumor growth of tamoxifen-resistant breast cancer via Pin1 inhibition. Food Chem. Toxicol. 2012;50:3625-3634.

    Not in our library10.1016/j.fct.2012.07.027

  131. 131.

    Evan G, Littlewood T. A matter of life and cell death. Science. 1998;281:1317-1322.

    Not in our library10.1126/science.281.5381.1317

  132. 132.

    Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature. 2004;432:307-315.

    Not in our library10.1038/nature03098

  133. 133.
    ShaPINg cell fate upon DNA damage:role of Pin1 isomerase in DNA damage-induced cell death and repair · 2014
    Not checked
  134. 134.

    Shen ZJ, Malter JS. Determinants of eosinophil survival and apoptotic cell death. Apoptosis. 2015;20:224-234.

    Not in our library10.1007/s10495-014-1072-2

  135. 135.

    Shen ZJ, Esnault S, Schinzel A, Borner C, Malter JS. The peptidyl-prolyl isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation. Nat. Immunol. 2009;10:257-265.

    Not in our library10.1038/ni.1697

  136. 136.

    Yang X, Khosravi-Far R, Chang HY, Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell. 1997;89:1067-1076.

    Not in our library10.1016/s0092-8674(00)80294-9

  137. 137.

    Helmke C, et al. Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8. Cell Res. 2016;26:914-934.

    Not in our library10.1038/cr.2016.78

  138. 138.

    Oh J, Malter JS. Pin1-FADD interactions regulate Fas-mediated apoptosis in activated eosinophils. J. Immunol. 2013;190:4937-4945.

    Not in our library10.4049/jimmunol.1202646

  139. 139.

    Ryo A, et al. A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx. J. Biol. Chem. 2007;282:36671-36681.

    Not in our library10.1074/jbc.m704145200

  140. 140.

    Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309-1312.

    Not in our library10.1126/science.281.5381.1309

  141. 141.

    Ding Q, et al. Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Res. 2008;68:6109-6117.

    Not in our library10.1158/0008-5472.can-08-0579

  142. 142.

    Basu A, Haldar S. Signal-induced site specific phosphorylation targets Bcl2 to the proteasome pathway. Int. J. Oncol. 2002;21:597-601.

    Not in our library

  143. 143.

    Lee YC, Chen YJ, Huang CH, Chang LS. Amsacrine-induced apoptosis of human leukemia U937 cells is mediated by the inhibition of AKT- and ERK-induced stabilization of MCL1. Apoptosis. 2017;22:406-420.

    Not in our library10.1007/s10495-016-1307-5

  144. 144.

    Wang T, Liu Z, Shi F, Wang J. Pin1 modulates chemo-resistance by up-regulating FoxM1 and the involvements of Wnt/β-catenin signaling pathway in cervical cancer. Mol. Cell. Biochem. 2016;413:179-187.

    Not in our library10.1007/s11010-015-2651-4

  145. 145.

    Namgoong GM, et al. The prolyl isomerase Pin1 induces LC-3 expression and mediates tamoxifen resistance in breast cancer. J. Biol. Chem. 2010;285:23829-23841.

    Not in our library10.1074/jbc.m109.092874

  146. 146.

    Cheng CW, et al. PIN1 inhibits apoptosis in hepatocellular carcinoma through modulation of the antiapoptotic function of survivin. Am. J. Pathol. 2013;182:765-775.

    Not in our library10.1016/j.ajpath.2012.11.034

  147. 147.

    Dourlen P, et al. The peptidyl prolyl cis/trans isomerase Pin1 downregulates the inhibitor of apoptosis protein Survivin. Biochim. Biophys. Acta. 2007;1773:1428-1437.

    Not in our library10.1016/j.bbamcr.2007.05.012

  148. 148.

    Bitomsky N, et al. Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc. Natl. Acad. Sci. USA. 2013;110:E4203-E4212.

    Not in our library10.1073/pnas.1310001110

  149. 149.

    Hilton BA, et al. ATR plays a direct antiapoptotic role at mitochondria, which is regulated by prolyl isomerase Pin1. Mol. Cell. 2015;60:35-46.

    Not in our library10.1016/j.molcel.2015.08.008

  150. 150.

    Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121:1-14.

    Not in our library10.1111/j.1365-2567.2007.02587.x

  151. 151.
    Sweeten PAMPs: role of sugar complexed PAMPs in innate immunity and vaccine biology · 2013
    No notice
  152. 152.

    Kwissa M, Nakaya HI, Oluoch H, Pulendran B. Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates. Blood. 2012;119:2044-2055.

    Not in our library10.1182/blood-2011-10-388579

  153. 153.

    Cao Z, Henzel WJ, Gao X. IRAK: a kinase associated with the interleukin-1 receptor. Science. 1996;271:1128-1131.

    Not in our library10.1126/science.271.5252.1128

  154. 154.

    Honda K, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005;434:772-777.

    Not in our library10.1038/nature03464

  155. 155.

    Tun-Kyi A, et al. Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon-mediated immunity. Nat. Immunol. 2011;12:733-741.

    Not in our library10.1038/ni.2069

  156. 156.

    Wei S, et al. Pin1-targeted therapy for systemic lupus erythematosus. Arthritis Rheumatol. 2016;68:2503-2513.

    Not in our library10.1002/art.39741

  157. 157.

    Huai W, et al. Mint3 potentiates TLR3/4- and RIG-I-induced IFN-β expression and antiviral immune responses. Proc. Natl. Acad. Sci. USA. 2016;113:11925-11930.

    Not in our library10.1073/pnas.1601556113

  158. 158.

    Saitoh T, et al. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat. Immunol. 2006;7:598-605.

    Not in our library10.1038/ni1347

  159. 159.

    Yang K, et al. TRIM21 is essential to sustain IFN regulatory factor 3 activation during antiviral response. J. Immunol. 2009;182:3782-3792.

    Not in our library10.4049/jimmunol.0803126

  160. 160.

    El Asmi F, et al. Implication of PMLIV in both intrinsic and innate immunity. PLoS Pathog. 2014;10:e1003975.

    Not in our library10.1371/journal.ppat.1003975

  161. 161.

    Osterlund PI, Pietilä TE, Veckman V, Kotenko SV, Julkunen I. IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes. J. Immunol. 2007;179:3434-3442.

    Not in our library10.4049/jimmunol.179.6.3434

  162. 162.

    Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137-143.

    Not in our library10.1016/j.it.2012.10.001

  163. 163.

    Koorella C, et al. Novel regulation of CD80/CD86-induced phosphatidylinositol 3-kinase signaling by NOTCH1 protein in interleukin-6 and indoleamine 2,3-dioxygenase production by dendritic cells. J. Biol. Chem. 2014;289:7747-7762.

    Not in our library10.1074/jbc.m113.519686

  164. 164.

    Chen W, Ten Dijke P. Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 2016;16:723-740.

    Not in our library10.1038/nri.2016.112

  165. 165.

    Yang JW, et al. Pin1 induction in the fibrotic liver and its roles in TGF-β1 expression and Smad2/3 phosphorylation. J. Hepatol. 2014;60:1235-1241.

    Not in our library10.1016/j.jhep.2014.02.004

  166. 166.

    Shen ZJ, et al. Pin1 regulates TGF-beta1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J. Clin. Invest. 2008;118:479-490.

    Not in our library10.1172/jci34527

  167. 167.

    Liu Y, et al. Manipulating PML SUMOylation via silencing UBC9 and RNF4 regulates cardiac fibrosis. Mol. Ther. 2017;25:666-678.

    Not in our library10.1016/j.ymthe.2016.12.021

  168. 168.
    Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution · 2018
    No notice
  169. 169.

    Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517:311-320.

    Not in our library10.1038/nature14191

  170. 170.

    Sfanos KS, Yegnasubramanian S, Nelson WG, De Marzo AM. The inflammatory microenvironmentand microbiome in prostate cancer development. Nat. Rev. Urol. 2017;15:11-24.

    Not in our library10.1038/nrurol.2017.167

  171. 171.

    Atsumi T, et al. Inflammation amplifier, a new paradigm in cancer biology. Cancer Res. 2014;74:8-14.

    Not in our library10.1158/0008-5472.can-13-2322

  172. 172.

    Leto TL, Geiszt M. Role of Nox family NADPH oxidases in host defense. Antioxid. Redox Signal. 2006;8:1549-1561.

    Not in our library10.1089/ars.2006.8.1549

  173. 173.

    Makni-Maalej K, et al. The TLR7/8 agonist CL097 primes N-formyl-methionyl-leucyl-phenylalanine-stimulated NADPH oxidase activation in human neutrophils: critical role of p47phox phosphorylation and the proline isomerase Pin1. J. Immunol. 2012;189:4657-4665.

    Not in our library10.4049/jimmunol.1201007

  174. 174.

    Boussetta T, et al. The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-alpha-induced priming of the NADPH oxidase in human neutrophils. Blood. 2010;116:5795-5802.

    Not in our library10.1182/blood-2010-03-273094

  175. 175.

    Xing Z, Ohkawara Y, Jordana M, Graham F, Gauldie J. Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions. J. Clin. Invest. 1996;97:1102-1110.

    Not in our library10.1172/jci118503

  176. 176.

    DeMaria CT, Brewer G. AUF1 binding affinity to A+U-rich elements correlates with rapid mRNA degradation. J. Biol. Chem. 1996;271:12179-12184.

    Not in our library10.1074/jbc.271.21.12179

  177. 177.

    Shen ZJ, Esnault S, Malter JS. The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat. Immunol. 2005;6:1280-1287.

    Not in our library10.1038/ni1266

  178. 178.

    Esnault S, Shen ZJ, Whitesel E, Malter JS. The peptidyl-prolyl isomerase Pin1 regulates granulocyte-macrophage colony-stimulating factor mRNA stability in T lymphocytes. J. Immunol. 2006;177:6999-7006.

    Not in our library10.4049/jimmunol.177.10.6999

  179. 179.

    Esnault S, et al. A critical role for Pin1 in allergic pulmonary eosinophilia in rats. J. Allergy Clin. Immunol. 2007;120:1082-1088.

    Not in our library10.1016/j.jaci.2007.06.024

  180. 180.

    Kim K, et al. Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation. Carcinogenesis. 2014;35:1352-1361.

    Not in our library10.1093/carcin/bgu044

  181. 181.

    Nechama M, et al. The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation. Nat. Commun. 2018;9:1603.

    Not in our library10.1038/s41467-018-03886-6

  182. 182.

    Jeong HG, et al. Novel role of Pin1 induction in type II collagen-mediated rheumatoid arthritis. J. Immunol. 2009;183:6689-6697.

    Not in our library10.4049/jimmunol.0901431

  183. 183.

    Cho YA, et al. PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses. J. Dent. Res. 2015;94:371-380.

    Not in our library10.1177/0022034514563335

  184. 184.

    Paneni F, et al. Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes. Eur. Heart J. 2015;36:817-828.

    Not in our library10.1093/eurheartj/ehu179

  185. 185.

    Nakatsu Y, et al. Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model. J. Biol. Chem. 2012;287:44526-44535.

    Not in our library10.1074/jbc.m112.397133

  186. 186.

    Asuri S, et al. Primary biliary cholangitis in British Columbia First Nations: clinical features and discovery of novel genetic susceptibility loci. Liver. Int. 2018;38:940-948.

    Not in our library10.1111/liv.13686

  187. 187.

    van Tiel CM, Kurakula K, Koenis DS, van der Wal E, de Vries CJ. Dual function of Pin1 in NR4A nuclear receptor activation: enhanced activity of NR4As and increased Nur77 protein stability. Biochim. Biophys. Acta. 2012;1823:1894-1904.

    Not in our library10.1016/j.bbamcr.2012.06.030

  188. 188.

    Poolman TM, Farrow SN, Matthews L, Loudon AS, Ray DW. Pin1 promotes GR transactivation by enhancing recruitment to target genes. Nucleic Acids Res. 2013;41:8515-8525.

    Not in our library10.1093/nar/gkt624

  189. 189.

    Yu L, et al. Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res. 2017;77:1564-1574.

    Not in our library10.1158/0008-5472.can-16-2074

  190. 190.

    Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029-1033.

    Not in our library10.1126/science.1160809

  191. 191.

    Lee N, Kim D. Cancer metabolism: fueling more than just growth. Mol. Cells. 2016;39:847-854.

    Not in our library10.14348/molcells.2016.0310

  192. 192.

    Wang CW, Purkayastha A, Jones KT, Thaker SK, Banerjee U. In vivo genetic dissection of tumor growth and the Warburg effect. eLife. 2016;5:e18126.

    Not in our library10.7554/elife.18126

  193. 193.

    Pate KT, et al. Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J. 2014;33:1454-1473.

    Not in our library10.15252/embj.201488598

  194. 194.

    Liu Z, et al. Nutrient deprivation-related OXPHOS/glycolysis interconversion via HIF-1α/C-MYC pathway in U251 cells. Tumour Biol. 2016;37:6661-6671.

    Not in our library10.1007/s13277-015-4479-7

  195. 195.
    Role of long non-coding RNAs in glucose metabolism in cancer · 2017
    No notice
  196. 196.

    Yang W, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat. Cell Biol. 2012;14:1295-1304.

    Not in our library10.1038/ncb2629

  197. 197.

    Yang W, et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature. 2011;480:118-122.

    Not in our library10.1038/nature10598

  198. 198.

    Hitosugi T, et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell. 2011;44:864-877.

    Not in our library10.1016/j.molcel.2011.10.015

  199. 199.

    Li X, et al. Mitochondria-translocated PGK1 functions as a protein kinase to coordinate glycolysis and the TCA cycle in tumorigenesis. Mol. Cell. 2016;61:705-719.

    Not in our library10.1016/j.molcel.2016.02.009

  200. 200.

    van der Mijn JC, Panka DJ, Geissler AK, Verheul HM, Mier JW. Novel drugs that target the metabolic reprogramming in renal cell cancer. Cancer Metab. 2016;4:14.

    Not in our library10.1186/s40170-016-0154-8

  201. 201.

    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071-1078.

    Not in our library10.1038/nature08467

  202. 202.

    Matt S, Hofmann TG. The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell. Mol. Life Sci. 2016;73:2829-2850.

    Not in our library10.1007/s00018-016-2130-4

  203. 203.

    Heyer WD, Ehmsen KT, Liu J. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet. 2010;44:113-139.

    Not in our library10.1146/annurev-genet-051710-150955

  204. 204.

    Sartori AA, et al. Human CtIP promotes DNA end resection. Nature. 2007;450:509-514.

    Not in our library10.1038/nature06337

  205. 205.

    Steger M, et al. Prolyl isomerase PIN1 regulates DNA double-strand break repair by counteracting DNA end resection. Mol. Cell. 2013;50:333-343.

    Not in our library10.1016/j.molcel.2013.03.023

  206. 206.

    Ferretti LP, Lafranchi L, Sartori AA. Controlling DNA-end resection: a new task for CDKs. Front. Genet. 2013;4:99.

    Not in our library10.3389/fgene.2013.00099

  207. 207.

    Burrell RA, et al. Replication stress links structural and numerical cancer chromosomal instability. Nature. 2013;494:492-496.

    Not in our library10.1038/nature11935

  208. 208.

    Waizenegger IC, Hauf S, Meinke A, Peters JM. Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell. 2000;103:399-410.

    Not in our library10.1016/s0092-8674(00)00132-x

  209. 209.

    Hellmuth S, et al. Human chromosome segregation involves multi-layered regulation of separase by the peptidyl-prolyl-isomerase Pin1. Mol. Cell. 2015;58:495-506.

    Not in our library10.1016/j.molcel.2015.03.025

  210. 210.

    Fabbro M, et al. Cdk1/Erk2- and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis. Dev. Cell. 2005;9:477-488.

    Not in our library10.1016/j.devcel.2005.09.003

  211. 211.

    van der Horst A, Khanna KK. The peptidyl-prolyl isomerase Pin1 regulates cytokinesis through Cep55. Cancer Res. 2009;69:6651-6659.

    Not in our library10.1158/0008-5472.can-09-0825

  212. 212.

    Estey MP, et al. Mitotic regulation of SEPT9 protein by cyclin-dependent kinase 1 (Cdk1) and Pin1 protein is important for the completion of cytokinesis. J. Biol. Chem. 2013;288:30075-30086.

    Not in our library10.1074/jbc.m113.474932

  213. 213.

    Suizu F, Ryo A, Wulf G, Lim J, Lu KP. Pin1 regulates centrosome duplication, and its overexpression induces centrosome amplification, chromosome instability, and oncogenesis. Mol. Cell. Biol. 2006;26:1463-1479.

    Not in our library10.1128/mcb.26.4.1463-1479.2006

  214. 214.

    Duensing S, Duensing A, Crum CP, Münger K. Human papillomavirus type 16 E7 oncoprotein-induced abnormal centrosome synthesis is an early event in the evolving malignant phenotype. Cancer Res. 2001;61:2356-2360.

    Not in our library

  215. 215.

    Prabhavathy D, Vijayalakshmi R, Kanchana MP, Karunagaran D. HPV16 E2 enhances the expression of NF-κB and STAT3 target genes and potentiates NF-κB activation by inflammatory mediators. Cell. Immunol. 2014;292:70-77.

    Not in our library10.1016/j.cellimm.2014.09.005

  216. 216.

    Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat. Rev. Cancer. 2005;5:275-284.

    Not in our library10.1038/nrc1590

  217. 217.

    Lee YC, et al. Pin1 acts as a negative regulator of the G2/M transition by interacting with the Aurora-A-Bora complex. J. Cell. Sci. 2013;126:4862-4872.

    Not in our library10.1242/jcs.121368

  218. 218.

    Cho YS, et al. TPA-induced cell transformation provokes a complex formation between Pin1 and 90 kDa ribosomal protein S6 kinase 2. Mol. Cell. Biochem. 2012;367:85-92.

    Not in our library10.1007/s11010-012-1322-y

  219. 219.

    Del Rosario JS, et al. Death associated protein kinase (DAPK)-mediated neurodegenerative mechanisms in nematode excitotoxicity. BMC Neurosci. 2015;16:25.

    Not in our library10.1186/s12868-015-0158-2

  220. 220.

    Zhang X, Zhang B, Gao J, Wang X, Liu Z. Regulation of the microRNA 200b (miRNA-200b) by transcriptional regulators PEA3 and ELK-1 protein affects expression of Pin1 protein to control anoikis. J. Biol. Chem. 2013;288:32742-32752.

    Not in our library10.1074/jbc.m113.478016

  221. 221.

    Lee KH, et al. MicroRNA-296-5p (miR-296-5p) functions as a tumor suppressor in prostate cancer by directly targeting Pin1. Biochim. Biophys. Acta. 2014;1843:2055-2066.

    Not in our library10.1016/j.bbamcr.2014.06.001

  222. 222.

    Li, J., et al. Pin1 impairs microRNA biogenesis by mediating conformation change of XPO5 in hepatocellular carcinoma. Cell Death Differ.10.1038/s41418-018-0065-z (2018).

    Not in our library10.1038/s41418-018-0065-z

  223. 223.

    Yang D, et al. A novel controlled release formulation of the Pin1 inhibitor ATRA to improve liver cancer therapy by simultaneously blocking multiple cancer pathways. J. Control Release. 2018;269:405-422.

    Not in our library10.1016/j.jconrel.2017.11.031

  224. 224.

    Marsolier J, et al. Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation. Nature. 2015;520:378-382.

    Not in our library10.1038/nature14044

  225. 225.

    Wang XJ, Xu B, Mullins AB, Neiler FK, Etzkorn FA. Conformationally locked isostere of phosphoSer-cis-Pro inhibits Pin1 23-fold better than phosphoSer-trans-Pro isostere. J. Am. Chem. Soc. 2004;126:15533-15542.

    Not in our library10.1021/ja046396m

  226. 226.

    Liu C, Mu C, Li Z, Xu L. Imazamethabenz inhibits human breast cancer cell proliferation, migration and invasion via combination with Pin1. Mol. Med. Rep. 2017;15:3210-3214.

    Not in our library10.3892/mmr.2017.6399

  227. 227.

    Pu, W., et al. Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development. Hepatology10.1002/hep.29819 (2018)

    Not in our library10.1002/hep.29819

  228. 228.

    Zheng M, et al. Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma. Oncotarget. 2017;8:29771-29784.

    Not in our library10.18632/oncotarget.15967

  229. 229.

    Sajadimajd S, Yazdanparast R. Sensitizing effect of juglone is mediated by down regulation of Notch1 signaling pathway in trastuzumab-resistant SKBR3 cells. Apoptosis. 2017;22:135-144.

    Not in our library10.1007/s10495-016-1291-9

  230. 230.

    Uchida T, et al. Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation. Chem. Biol. 2003;10:15-24.

    Not in our library10.1016/s1074-5521(02)00310-1

  231. 231.

    Guo C, et al. Structure-based design of novel human Pin1 inhibitors (I). Bioorg. Med. Chem. Lett. 2009;19:5613-5616.

    Not in our library10.1016/j.bmcl.2009.08.034

  232. 232.

    Dong L, et al. Structure-based design of novel human Pin1 inhibitors (II). Bioorg. Med. Chem. Lett. 2010;20:2210-2214.

    Not in our library10.1016/j.bmcl.2010.02.033

  233. 233.

    Zhang Y, et al. Structural basis for high-affinity peptide inhibition of human Pin1. ACS Chem. Biol. 2007;2:320-328.

    Not in our library10.1021/cb7000044

  234. 234.

    Potter AJ, et al. Structure-guided design of alpha-amino acid-derived Pin1 inhibitors. Bioorg. Med. Chem. Lett. 2010;20:586-590.

    Not in our library10.1016/j.bmcl.2009.11.090

  235. 235.

    Urusova DV, et al. Epigallocatechin-gallate suppresses tumorigenesis by directly targeting Pin1. Cancer Prev. Res. (Phila.). 2011;4:1366-1377.

    Not in our library10.1158/1940-6207.capr-11-0301

  236. 236.

    Cui G, et al. Synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors. Bioorg. Med. Chem. 2018;26:2186-2197.

    Not in our library10.1016/j.bmc.2018.03.024

  237. 237.

    Bedewy W, et al. Generation of a cell-permeable cycloheptapeptidyl inhibitor against the peptidyl-prolyl isomerase Pin1. Org. Biomol. Chem. 2017;15:4540-4543.

    Not in our library10.1039/c7ob00430c

  238. 238.

    Lim TG, et al. The prolyl isomerase Pin1 is a novel target of 6,7,4′-trihydroxyisoflavone for suppressing esophageal cancer growth. Cancer Prev. Res. (Phila.). 2017;10:308-318.

    Not in our library10.1158/1940-6207.capr-16-0318

  239. 239.

    Cho JH, Chae JI, Shim JH. Rhein exhibits antitumorigenic effects by interfering with the interaction between prolyl isomerase Pin1 and c-Jun. Oncol. Rep. 2017;37:1865-1872.

    Not in our library10.3892/or.2017.5434

  240. 240.

    Zhao H, Cui G, Jin J, Chen X, Xu B. Synthesis and Pin1 inhibitory activity of thiazole derivatives. Bioorg. Med. Chem. 2016;24:5911-5920.

    Not in our library10.1016/j.bmc.2016.09.049

  241. 241.

    Wu KJ, et al. Small molecule Pin1 inhibitor blocking NF-κB signaling in prostate cancer cells. Chem. Asian J. 2017;13:275-279.

    Not in our library10.1002/asia.201701216

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