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Glycogen synthase kinase 3 beta: can it be a target for oral cancer

Rajakishore Mishra

Molecular Cancer · 2010 · Review

Abstract

Despite progress in treatment approaches for oral cancer, there has been only modest improvement in patient outcomes in the past three decades. The frequent treatment failure is due to the failure to control tumor recurrence and metastasis. These failures suggest that new targets should be identified to reverse oral epithelial dysplastic lesions. Recent developments suggest an active role of glycogen synthase kinase 3 beta (GSK3 beta) in various human cancers either as a tumor suppressor or as a tumor promoter. GSK3beta is a Ser/Thr protein kinase, and there is emerging evidence that it is a tumor suppressor in oral cancer. The evidence suggests a link between key players in oral cancer that control transcription, accelerated cell cycle progression, activation of invasion/metastasis and anti-apoptosis, and regulation of these factors by GSK3beta. Moreover, the major upstream kinases of GSK3beta and their oncogenic activation by several etiological agents of oral cancer support this hypothesis. In spite of all this evidence, a detailed analysis of the role of GSK3beta in oral cancer and of its therapeutic potential has yet to be conducted by the scientific community. The focus of this review is to discuss the multitude of roles of GSK3beta, its possible role in controlling different oncogenic events and how it can be targeted in oral cancer.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Oral cancer is the sixth most common cancer in the world, and its incidence varies in different ecogeographic regions. Its occurrence is associated with exposure to smoking and alcohol consumption in the Western population. The majority of cases occur in Asia, where it is mainly associated with betel quid chewing. Poor oral hygiene and human papillomavirus (HPV) infection of oral epithelial cells are other etiological factors. In addition to genetic differences, other etiological factors promote the occurrence of this disease to different extents in different populations. Although there are several differences in disease occurrence and etiology between populations, there is one aspect of these tumors that is highly similar worldwide. Oral tumors are mainly asymptomatic initially, are aggressive, and frequently invade and migrate to distant organs, making them difficult to treat. This suggests that, although different predisposing factors activate various molecular pathways, eventually all of them may follow a common path thereafter to result in oral cancer.

2Advances in recent decades in the surgical, radiotherapeutic and chemotherapeutic treatment of oral cancer have only modestly improved patient survival. Various approaches have been used for the clinical treatment of oral cancer patients in the last three decades, from non-targeted chemotherapy to highly targeted pharmacological inhibitors and specific monoclonal antibodies. Although targeted therapies yield better outcomes than non-targeted therapies, frequent treatment failure suggests the need for new treatments or targets for this disease. In oral cancer, active transcription of various genes leads to rapid cell division, faster invasion and reduction of cell death. Although it has been largely overlooked, there is a potential link between key players in oral cancer, including transcription factors, cell cycle regulators, invasion/metastasis-promoting factors, and cell survival regulators, and their regulation under the control of glycogen synthase kinase 3β (GSK3β).

3GSK3β plays a major role in epithelial cell homeostasis. Its activity is regulated by site-specific phosphorylation of Tyr216/Ser9 residues. The regulated phosphorylation of Ser9GSK3β is the main cause of various pathological conditions, and it is upregulated in epithelial cancers. Many upstream kinases protein kinase A (PKA), Akt/PKB, PKC, p90 ribosomal S6 kinase/MAPK-activating protein (p90RSK/MAPKAP) and p70 ribosomal S6 kinase (p70S6K) are known to phosphorylate Ser9 of GSK3β, depending on the cellular context and various upstream regulators. The oncogenic activation of these upstream signaling molecules is frequently reported in oral squamous cell carcinoma (OSCC). Many of these oncogenic pathways are activated by common etiological factors of this cancer. Overall, this evidence suggests the possible active involvement of GSK3β-mediated signaling in this neoplastic disease. This review attempts to correlate the established pathways of oral cancer with GSK3β signaling and discusses the potential of this kinase as a therapeutic target.

The GSK3 family and its regulation

4GSK3 was discovered nearly three decades ago in rabbit skeletal muscle as a protein kinase that phosphorylates and inactivates glycogen synthase, the final enzyme of glycogen biosynthesis. GSK3 is a multifunctional Ser/Thr kinase with diverse roles in various human diseases, including diabetes, inflammation, neurological disorders and various neoplastic diseases. To date, two members of the mammalian GSK3 family (α and β) are known. They are ubiquitously expressed and highly conserved and are members of the CMGC family of protein kinases. Many of the substrates of GSK3 need a "priming phosphate" (which is a Ser/Thr residue) located four amino acids (aa) C-terminally from the site of phosphorylation. GSK3 is constitutively active in resting cells and undergoes a rapid and transient inhibition in response to a number of external signals. Physiological regulation of GSK3 activity by various upstream kinases in different physiological and pathological condition is established.

GSK3β and its role in tumorigenesis

5GSK3β drives oncogenic progression either by its inhibition or its activation, depending on the cell type. In recent years, its role in cancer has become firmly established. The differences in the roles of GSK3β depending on the type of cancer are quite interesting. Whereas it has a growth-promoting role in some cancers, it suppresses growth in others. Based on the literature, it is clear that GSK3β can act either as a tumor promoter or as a tumor suppressor, as shown in Table 1.

GSK3β and its control over transcription

6Alteration of the transcriptional machinery is common in neoplastic diseases, including oral cancer. Oncogenic transcription factors (OTFs) alter the transcriptional machinery to regulate mRNA synthesis. GSK3β regulates the stability of various oncogenic TFs like the activator protein 1 (AP-1), nuclear factor kappa B (NFκB), c-Myc, β-catenin, Snail, Forkhead (FH), CAAT-enhancer binding protein (C/EBPs), and cAMP response element-binding (CREB) by phosphorylation. Most of these TFs are physiological targets of GSK3β that undergo proteasomal degradation upon phosphorylation. AP-1 transcriptional activity is high in oral cancer tissue samples. Active GSK3β directly phosphorylates c-Jun at Thr239 which promotes its degradation. It is also known that in normal oral mucosa c-Jun is localized in the cytoplasm while it enters to the nucleus at the onset of oral carcinogenesis. Both Fos and Jun are phosphorylated and activated by mitogen activated protein kinase (MAPK) and c-Jun n-terminal kinase (JNK) kinase system may be due to inactive GSK3β. Moreover the expressions of p65 (one of the NFκB family member) have been observed in oral cancer tissue samples and metastatic OSCC. GSK3β phosphorylates p65 at Ser468 and negatively regulate its activity by promoting its degradation. p65 might escape from its turnover because of inactivated GSK3β in OSCC. Recent report suggests active GSK3β physically interact with IκBα in normal epithelial cells. Moreover study in different system suggests that active GSK3β blocks NFκB dependent transcription, by preventing IκBα degradation. In normal epithelial cells NFκB activity is known to be inhibited by GSK3. From all these evidences, it seems like NFκB activation in OSCC may be modulated, because of inactive GSK3β like that in other epithelial cancers. On the other hand, degradation of c-Myc and β-catenin is initiated by phosphorylation of GSK3β. The overexpression of c-Myc and β-catenin protein in OSCC is established. The gene mutation on hot spots i.e. Thr58 of c-Myc and Ser33, Ser37, Thr41 and Ser45 of β-catenin abolishes phosphorylation by GSK3β results in preventing ubiquitination and proteasome mediated degradation of c-Myc/β-catenin has been reported in various cancers but not so far in OSCC. In OSCC, c-Myc/β-catenin protein might get stability not because of missense mutation at these hot spot codons but because of inactivation of its phosphorylating kinase i.e. GSK3β it self. The activated Snail has been reported in OSCC. GSK3β is well known regulator of Snail which phosphorylates and that leads to Snail nuclear export and deregulation. Moreover, p53 is highly involved in OSCC. Though it is inactivated by mutation in nearly half of oral cancer population the cause of its inactivation is still doubtful in the other half. p53 activity is regulated by active GSK3β, due to either physical association or phosphorylation and post-translational modification. It is possible that in OSCC cases without p53 mutations, p53 can be inactivated due to inactive GSK3β. These OTFs those are important in OSCC and are directly regulated possibly by GSK3β. Alteration of these TFs plays a vital role in various diseases, including OSCC.

GSK3β is a key player in OSCC

7GSK3β can promote or suppress growth in different types of cancer (Table 1). The inactivation of GSK3β has been reported in most cancers of epithelial origin, such as skin, breast, and in cancers of the oral cavity, salivary glands, larynx, and esophagus. The basal level of inactivated GSK3β (pSer9GSK3β) in OSCC cell lines is very high but can be decreased by inhibiting the GSK3β upstream inactivating pathway. A recent report suggests that activating GSK3β can reverse the epithelial-mesenchymal process in oral cancer. GSK3β-mediated signaling could explain numerous molecular disorders specific to oral cancer.

A) Cell cycle regulation

8Cell division is a precisely regulated process that occurs obligatorily in all organisms. The ability of cells to divide is mainly attributed to the presence of three classes of molecules: CDKs (Cyclin Dependent Kinases, a family of Ser/Thr kinases), their binding partners cyclins and CDK inhibitors (CDKI). The transcriptional and post-translational regulation of cyclin D1 and of cyclin E in OSCC are well documented. Cyclin D1/E transcriptional upregulation is achieved by regulating TFs (e.g., AP-1, NFκB, β-catenin), and protein stability/nuclear accumulation are also increased in OSCC. Inactive GSK3β prevents the phosphorylation of Thr286 cyclin D1 and Ser380 cyclin E, which blocks their nuclear export and degradation. An inverse correlation between cyclin D1 and GSK3β expression has been reported in oral cancer. Cyclin A and cyclin B are also overexpressed in OSCC. These cyclins are primarily regulated by c-Myc and p53 and thus qualify as GSK3β targets. Because these are S phase- and G2-M phase-specific cyclins, their expression is affected by the G1 phase-specific cell cycle events of cyclin D1/CDK4 and cyclin E/CDK2 activation. Overexpression of CDK4 mRNA has been reported in different malignancies, including oral and epithelial cancer. c-Myc controls the expression of CDK4 by binding to E-box elements present in its promoter that are not only overexpressed in OSCC but also are regulated by GSK3β. p21 (WAF1/CIP1) competes with cyclins for binding to CDKs, and its expression is usually decreased in various cancers. However, in OSCC, the overexpression of p21 (WAF1/CIP1) is quite evident, and its overexpression significantly correlates with tumor size, lymph node involvement and clinical stage. Active GSK3β directly regulates p21 expression by phosphorylation at Thr57, leading to proteasome-mediated degradation. Another explanation could be that the TFs C/EBPα and -β (which may also be stabilized because of inactive GSK3β in OSCC) interact with p21 and protect it from degradation. The possible explanations for why p21 does not halt OSCC progression are numerous. One possible explanation is that p21 is inactivated by binding to the E7 protein of human papillomavirus 16 (HPV16), which is highly prevalent in OSCC. This association of p21 and E7 blocks the ability of p21 to inhibit cyclin/CDK activity as well as PCNA-dependent DNA synthesis. In contrast, another CDKI, p27, is reportedly down-regulated in OSCC in a process that might be mediated by forkhead (FH) TF. In breast cancer (where active GSK3β acts like a tumor suppressor as in OSCC; Table 1) knock down of PI3K promotes degradation of FH and p27 possibly via GSK3β activation. GADD45 and GADD153 are checkpoint inhibitors and tumor suppressors that have roles in multiple tumor types, including OSCC. GADD45 is also controlled by p53, and upon DNA damage, it is activated to arrest the cell cycle. Both GADD45 and GADD153 are downstream targets of c-Myc and thus qualify as possible GSK3β targets in OSCC. Cell division cycle 25A (CDC25A) is also controlled by c-Myc. Direct evidence suggests a positive correlation between pSer9GSK3β and CDC25A expression in tumors of the oral cavity, salivary glands and larynx (Ref. and Fig 1).

B) Nodal invasion by epithelial-mesenchymal transition

9OSCC is a cancer of epithelial cells that invades surrounding tissues and frequently migrates to distant organs (metastasizes). The extra cellular matrix (ECM) interaction is important for the survival of normal epithelial cells but this interaction is gradually lost in squamous cell carcinoma. The major ECM molecules implicated in OSCC development include collagen, fibronectin, tenascin and laminin. Many ECM molecules are indirect targets of GSK3β via Snail- or AP-1. The degradation of basement membrane (collagen) by MMPs and its regulation by inactive GSK3β have been reported. Focal adhesion kinase (FAK) is overexpressed in preinvasive and invasive OSCC. Upregulation of FAK leads to migration, and its regulation by active NFκB is known in tongue squamous cell carcinoma cells (SCC25) possibly via inactive GSK3β. Another group of molecules, the integrins, are transmembrane, heterodimeric, cell-surface proteins (consisting of one α and one β subunit) that primarily function as cell adhesion molecules but also participate in signal transduction leading to cell migration, growth and oncogenesis. Human integrins are upregulated in OSCC, and they are primarily controlled by those transcription factors regulated by GSK3β. Recent evidence suggests a role for Snail in controlling multiple α/β-integrins and EMT in OSCC.

10MMPs are a group of extracellular matrix/basement-degrading proteases. High levels of MMP-2, -3, and -9 have been associated with poor prognosis for patients with oral cancer, including the development of lymph node metastasis and poor survival. The transcriptional activation of MMP-1,-3, and -9 is common in OSCC, and they are all targets of AP-1, NFκB, C/EBPs or Snail, highlighting the importance of GSK3β-mediated signaling in the oral cancer invasion program.

11Cadherins interact with the actin cytoskeleton to maintain tissue architecture. In some cancers, including OSCC, loss of E-cadherin favors invasion. An inverse correlation between E-cadherin and Snail expression has been reported in OSCC and epithelial cancers, which supports the regulation of E-cadherin by the inactivation of GSK3β and Snail. Snail represses E-cadherin gene expression in epithelial tumours. GSK3β is well known regulator of Snail which phosphorylates and that leads to Snail nuclear export and deregulation. Recent findings suggest that the forced activation of GSK3β and the resultant phosphorylation and cytoplasmic translocation of Snail lead to E-cadherin up-regulation, which can potentially reverse EMT in OSCC. Yang et al. have shown that EMT phenotypes can be decreased in head and neck SCC (HNSCC) by the use of siRNA-mediated repression of Snail or by the use of inhibitors of PI3K, which is a GSK3β-inactivating upstream kinase. On the other hand, elevated Cox-2 levels have been reported in various human malignancies, including OSCC. Inhibition of Cox-2 decreases integrin and MMP levels as well as the invasiveness of OSCC. Cox-2 gene transcription is controlled by wild-type p53 protein and by NFκB in betel quid-associated oral cancer, indirectly supporting the importance of inactive GSK3β (Ref and Fig 2).

C) Anti-Apoptosis

12The inhibition of apoptosis is a major cause of neoplastic disorders and an integral part of oral cancer pathogenesis. Abundant evidence suggests a possible role for active GSK3β in cell survival and apoptosis. Apoptosis is controlled by either the intrinsic (mitochondrial) or extrinsic pathway (activation of procaspase-8).

13Higher levels of Bcl-2 and lower levels of Bax are frequently reported in oral cancer. A recent report suggests that, in an OSCC cell line, Bcl-2 expression is affected even by slight changes in the status of pSer9GSK3β. Active GSK3β blocks CREB-dependent expression of the anti-apoptotic protein Bcl-2. Additionally, active GSK3β regulates p53 activity, which increases Bax protein levels to initiate apoptosis. Modulation of GSK3β can markedly increase p53-dependent activation of Bax, leading to cytochrome c release, loss of mitochondrial membrane potential and caspase-9 processing. Moreover, the physiological effect of p53 is governed by inactivation of GSK3β (pSer9 GSK3β) (and not by pTyr216GSK3β). Inhibition of Akt (a well-known kinase upstream of GSK3β) can only induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -mediated apoptosis by regulating the levels of Bcl-2 and Bax in OSCC. All of this evidence suggests that the survival advantage of OSCC cells over the normal oral epithelium might be due to progressive inactivation of GSK3β, which could be responsible for an increased Bcl-2/Bax protein ratio.

14On the other hand, oral cancer cells are resistant to cell death mediated by TRAIL, which can be achieved only by inactivation of the GSK3-inactivating PI3K/Akt pathway. Additionally, inhibition of caspase-8 reduces PI3K inhibitor-mediated apoptosis in OSCC. In the extrinsic apoptotic pathway, active GSK3β promotes the activation of the initiator caspase-8. Therefore, active GSK3β targets both intrinsic and extrinsic pathways to maintain control over growth and proliferation in normal epithelium by promoting apoptosis [Fig. 3]. This control might be disrupted in OSCC.

Oral cancer therapy and role of GSK3β signaling

15The inhibition of GSK3β is regulated by various upstream kinases (PKA, PKB/Akt, PKC, p90RSK/MAPKAP, p70RS6K). PKA is predominantly controlled by extracellular signals (epidermal growth factor: EGF, platelet derived growth factor: PDGF), carcinogens and second messengers, mainly c-AMP. PKA activation in an OSCC cell line has been reported. PKA-anchoring protein 220 (PKAP220) binds to both PKA and GSK3, bringing GSK3 into close proximity with PKA, which phosphorylates GSK3β to block its activity. Recently, PKA has been identified as a therapeutic target in HNSCC; moreover, inhibition of PKA is known to affect many molecules (e.g., NFκB, Cyclin D1, Bcl-2, Cox-2 and p21), most of which are direct/indirect targets of GSK3β. On the other hand, the activation of the PI3K/Akt pathway has been well studied in OSCC. Direct evidence suggests that the pSer9GSK3β level in OSCC cell line is very high and can be decreased by inhibiting Akt signaling. In addition, in oral cancer cells, blocking PI3K/Akt signaling causes more cells to undergo apoptosis; this effect is reversed by the use of a GSK3β inhibitor. Akt signaling is important in HNSCC and is considered as a potential therapeutic target. There is also evidence of PKC signaling in OSCC, and inhibition of PKC by pharmacological inhibitors reduces MMP-2 and MMP-9, possibly via GSK3β. Suppression of PKC activity promotes GSK3β activity in epithelial cells, which increases apoptosis. Targeting of PKCε has shown promising results in decreasing the invasion and mortality of HNSCC. Moreover, p90RSK is known for its role in epithelial cell motility and invasiveness. Tumor-promoting phorbol esters inhibit GSK3β via a classical MAPK cascade by activating p90RSK (MAPKAP-KI). Therefore, the role of the p90RSK/GSK3β pathway might be important in oral cancer. Finally, GSK3β is inactivated by the mammalian target of rapamycin (mTOR) pathway, in which p70S6K phosphorylates GSK3β. In a SCC cell line, EGF inactivates GSK3β, which can be reversed by rapamycin at a concentration that blocks the activation of p70S6K. Epidermal growth factor receptor (EGFR) activation in OSCC might activate the p70S6K pathway. Moreover, in HNSCC, p70S6K is reportedly very active, and targeting it with rapamycin has a potential anti-tumor effect in vivo, possibly due to the activation of GSK3β. All of these signaling pathways may have definite oncogenic properties and are activated by a variety of carcinogens or other cancer-promoting factors to induce oral cancer or cancers of similar epithelial origin. However, one thing that these oncogenic pathways share is that they all impinge on GSK3β inactivation. This may be the reason why, beyond geographical boundaries, all oral cancers are similar in their aggressiveness and their potential for migration and metastasis. Crosstalk is abundant in signal transduction pathways. Therefore, although targeting each of these pathways has a modest impact on oral cancer and causes toxicity to the patient, targeting GSK3β directly may be highly beneficial in treating OSCC [Fig. 4].

Oral cancer etiology and intracellular signaling

16The activation of established GSK3-inactivating upstream biological pathways by oral cancer-predisposing factors, such as tobacco, alcohol, and HPV, support the proposition of a causative role for GSK3β in OSCC. The role of carcinogens (from chewing and smoking tobacco) in oral cancer is firmly established. Smokers show elevated levels of adenyle cyclase (AC) and PKA activity in oral epithelial cells. Chewing areca nuts can lead to DNA damage and increased oxidative stress. The lime (calcium hydroxide) that coats the betel leaf promotes an alkaline oral environment, which activates Akt signaling. There is accumulating evidence that connects nicotine-induced tumorigenesis to the activation of MAPK signaling, activation of PI3K/Akt signaling and blocking of cytochrome c-mediated apoptosis. Alcohol abuse increases the permeability of cells to carcinogens and activates PKA in cell culture. HPV activates Akt in epithelial keratinocytes. Moreover, a recent evaluation of epithelial tumors suggests that HPV infection can alter many biological pathways to maintain malignant processes by decreasing focal adhesion and up-regulating Wnt signaling and cell cycle genes. Therefore, it is logical to hypothesize that the inactivation of GSK3β contributes to oral cancer.

Evaluation of therapeutic potential and possible methods of targeting GSK3β in OSCC

17Before selecting GSK3β as a therapeutic target in OSCC, its biological functions should be explored in detail. Though GSK3β has several isoforms, the isoform(s) specifically expressed in OSCC remain to be identified. If multiple isoforms are expressed, it will be important to understand their respective functions in oral cancer pathogenesis. The upstream cause of activation or inactivation of GSK3β as well as downstream target molecules and their status in OSCC should be thoroughly investigated at the patient level. Because it is an enzyme involved in regulating growth, cell cycle progression, apoptosis, and invasion, GSK3β may qualify as an ideal therapeutic target for OSCC. Because of its role in both extrinsic and intrinsic apoptotic pathways, and because active GSK3β is nontoxic to non-cancerous cells (e.g., in a knock-in mouse study replacing Ser9 of GSK3β with Ala), targeting the GSK3β pathway might be helpful in reducing unwanted apoptosis (in normal cells) and increasing useful apoptosis (in cancer cells).

18The activation status of upstream molecules and the inactivation of GSK3β should be tested in different patients because each patient has a different lifestyle, etiological factors and genetic abnormalities. GSK3β can be inactivated by different upstream molecules in different oral tumors, even in the same patient. Inhibiting the upstream molecules pharmacologically by using peptide competitors and blocking phosphorylation at Ser9 certainly will keep GSK3β in an active state. The crystal structure of GSK3β peptide with an activated Akt ternary complex has been reported. This may enable the design of small molecules that will disrupt the interaction of upstream kinases and GSK3β [Therapeutic strategy-I, Fig. 4] and thus prevent inhibitory kinases from associating with GSK3β. After checking the status of those patients who have inactivated GSK3β, Adenoviral vector carrying Ala9GSK3β may be tested along with other (chemo/radio) therapy, or with Ad-p53 (WT), which is known to block the progression of oral cancer to a certain extent. However, although the chances are remote, some OSCC tumors will contain active GSK3β. It will be easy to test the inhibitors of GSK3 in these cases. The use of LiCl and SB-216763 in ovarian cancer; LiCl and TDZD-8 in prostate cancer; TDZD-8, SB-216763 and AR-A014418 in colorectal cancer; LiCl, SB-216763, and TDZD-8 in myeloma; TDZD-8 in AML and AML progenitor and stem cell cancer; and LiCl and AR-A014418 in pancreatic cancer has been evaluated, with positive outcomes. Almost all GSK3 inhibitors are able to inhibit two isoforms of GSK3 (α & β) with similar potency. The production and clinical evaluation of small-molecule inhibitors of particular isoforms will improve the chances of successful treatment in the future. Recent advancements in molecular biology have proven the effectiveness of small RNA interference (RNAi) in reducing the level of one protein by promoting mRNA degradation. This has been tried in an animal model of OSCC and as an alternative therapeutic strategy in patients who have developed drug resistance. Similarly, RNAi has been used to counteract the overexpression of GSK3β in pancreatic, gastrointestinal, and prostate cancer, and it may be tried for OSCC.

Conclusion

19The goal of cancer drug discovery is to design non-toxic therapeutics that will be free of side effects. Thanks to a deepening understanding of cell biology and technological advancements, the concept of cancer therapy is being fine-tuned every day. Beginning with metabolic enzyme targeting using folate and methotrexate, to targeting of DNA polymerase and topoisomerase (tamoxifen), to selective hormonal targeting of estrogens/androgens via their nuclear hormone receptors, to the more recent advancement of targeting human growth factor receptor kinases and their effectors, the gradual improvements in our understanding of cancer biology have led to new and numerous therapeutics. Recent developments in molecular research have led to the hypothesis of "oncogene addiction," which suggest the continuous dependence of tumor cells on these oncogenes. The inactivation of GSK3β in OSCC may behave like an oncogene, and its gradual/sustained inactivation may promote oral cancer. Though most of the upstream and downstream targets and their expression status correlate with the understanding of GSK3β inactivation, real, direct assessment should be attempted. If the activated form of GSK3β is non-toxic to normal oral epithelial cells, as was found in animal models, then the manipulation of the activated GSK3β provides hope for treating oral cancer. Unlike other molecules, GSK3β is one of the most attractive targets and is well understood because of extensive prior research on it. Therefore, it should be evaluated thoroughly as a potential target for the treatment of oral cancer.

Competing interests

20The authors declare that they have no competing interest.

Authors' contributions

21RM reviewed the literature, drafted and finalized the manuscript.

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Pulverer BJ Kyriakis JM Avruch J Nikolakaki E Woodgett JR Phosphorylation of c-jun mediated by MAP kinasesNature1991 353670674
Not in our library10.1038/353670a0
34.
Chen RH Juo PC Curran T Blenis J Phosphorylation of c-Fos at the C-terminus enhances its transforming activityOncogene1996 1214931502
Not in our library
35.
Mishra A Bharti AC Varghese P Saluja D Das BC Differential expression and activation of NF-kappaB family proteins during oral carcinogenesis: Role of high risk human papillomavirus infectionInt J Cancer2006 11928402850
Not in our library10.1002/ijc.22262
36.
Sasahira T Kirita T Oue N Bhawal UK Yamamoto K Fujii K Ohmori H Luo Y Yasui W Bosserhoff AK Kuniyasu H High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinomaCancer Sci2008 9918061812
Not in our library10.1111/j.1349-7006.2008.00894.x
37.
Ma Y Wang M Li N Wu R Wang X Bleomycin-induced nuclear factor-kappaB activation in human bronchial epithelial cells involves the phosphorylation of glycogen synthase kinase 3betaToxicol Lett2009 187194200
Not in our library10.1016/j.toxlet.2009.02.023
38.
Sanchez JF Sniderhan LF Williamson AL Fan S Chakraborty-Sett S Maggirwar SB Glycogen synthase kinase 3beta-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kappaB signalingMol Cell Biol2003 2346494662
Not in our library10.1128/mcb.23.13.4649-4662.2003
39.
Bachelder RE Yoon SO Franci C de Herreros AG Mercurio AM Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transitionJ Cell Biol2005 1682933
Not in our library10.1083/jcb.200409067
40.
Tian D Zhu M Chen WS Li JS Wu RL Wang X Role of glycogen synthase kinase 3 in squamous differentiation induced by cigarette smoke in porcine tracheobronchial epithelial cellsFood Chem Toxicol2006 4415901596
Not in our library10.1016/j.fct.2006.03.013
41.
Vora HH Shah NG Trivedi TI Goswami JV Shukla SN Shah PM Expression of C-Myc mRNA in squamous cell carcinoma of the tongueJ Surg Oncol2007 957078
Not in our library10.1002/jso.20675
42.
Baral R Patnaik S Das BR Co-overexpression of p53 and c-myc proteins linked with advanced stages of betel- and tobacco-related oral squamous cell carcinomas from eastern IndiaEur J Oral Sci1998 106907913
Not in our library10.1046/j.0909-8836.1998.eos106502.x
43.
Mahomed F Altini M Meer S Altered E-cadherin/beta-catenin expression in oral squamous carcinoma with and without nodal metastasisOral Dis2007 13386392
Not in our library10.1111/j.1601-0825.2006.01295.x
44.
Tanaka N Odajima T Ogi K Ikeda T Satoh M Expression of E-cadherin, alpha-catenin, and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinomaBr J Cancer2003 89557563
Not in our library10.1038/sj.bjc.6601124
45.
Bankfalvi A Krassort M Vegh A Felszeghy E Piffko J Deranged expression of the E-cadherin/beta-catenin complex and the epidermal growth factor receptor in the clinical evolution and progression of oral squamous cell carcinomasJ Oral Pathol Med2002 31450457
Not in our library10.1034/j.1600-0714.2002.00147.x
46.
de Castro J Gamallo C Palacios J Moreno-Bueno G Rodriguez N Feliu J Gonzalez-Baron M beta-catenin expression pattern in primary oesophageal squamous cell carcinoma. Relationship with clinicopathologic features and clinical outcomeVirchows Arch2000 437599604
Not in our library10.1007/s004280000266
47.
Bahram F von der Lehr N Cetinkaya C Larsson LG c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnoverBlood2000 9521042110
Not in our library
48.
Oster SK Ho CS Soucie EL Penn LZ The myc oncogene: MarvelouslY ComplexAdv Cancer Res2002 8481154full_text
Not in our library10.1016/s0065-230x(02)84004-0
49.
Gregory MA Qi Y Hann SR Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localizationJ Biol Chem2003 2785160651612
Not in our library10.1074/jbc.m310722200
50.
DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein · 2008
Not checked
51.
Sogabe Y Suzuki H Toyota M Ogi K Imai T Nojima M Sasaki Y Hiratsuka H Tokino T Epigenetic inactivation of SFRP genes in oral squamous cell carcinomaInt J Oncol2008 3212531261
Not in our library10.3892/ijo_32_6_1253
52.
Iwai S Katagiri W Kong C Amekawa S Nakazawa M Yura Y Mutations of the APC, beta-catenin, and axin 1 genes and cytoplasmic accumulation of beta-catenin in oral squamous cell carcinomaJ Cancer Res Clin Oncol2005 131773782
Not in our library10.1007/s00432-005-0027-y
53.
Yeh KT Chang JG Lin TH Wang YF Chang JY Shih MC Lin CC Correlation between protein expression and epigenetic and mutation changes of Wnt pathway-related genes in oral cancerInt J Oncol2003 2310011007
Not in our library
54.
Franz M Spiegel K Umbreit C Richter P Codina-Canet C Berndt A Altendorf-Hofmann A Koscielny S Hyckel P Kosmehl H Virtanen I Expression of Snail is associated with myofibroblast phenotype development in oral squamous cell carcinomaHistochem Cell Biol2009 131651660
Not in our library10.1007/s00418-009-0559-3
55.
Zhou BP Deng J Xia W Xu J Li YM Gunduz M Hung MC Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transitionNat Cell Biol2004 6931940
Not in our library10.1038/ncb1173
56.
Doble BW Woodgett JR Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitionsCells Tissues Organs2007 1857384
Not in our library10.1159/000101306
57.
Oren M Decision making by p53: life, death and cancerCell Death Differ2003 10431442
Not in our library10.1038/sj.cdd.4401183
58.
Watcharasit P Bijur GN Song L Zhu J Chen X Jope RS Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53J Biol Chem2003 2784887248879
Not in our library10.1074/jbc.m305870200
59.
Eom TY Jope RS GSK3 beta N-terminus binding to p53 promotes its acetylationMol Cancer2009 814
Not in our library10.1186/1476-4598-8-14
60.
Ma C Wang J Gao Y Gao TW Chen G Bower KA Odetallah M Ding M Ke Z Luo J The role of glycogen synthase kinase 3beta in the transformation of epidermal cellsCancer Res2007 6777567764
Not in our library10.1158/0008-5472.can-06-4665
61.
Chun KH Lee HY Hassan K Khuri F Hong WK Lotan R Implication of protein kinase B/Akt and Bcl-2/Bcl-XL suppression by the farnesyl transferase inhibitor SCH66336 in apoptosis induction in squamous carcinoma cellsCancer Res2003 6347964800
Not in our library
62.
Amornphimoltham P Sriuranpong V Patel V Benavides F Conti CJ Sauk J Sausville EA Molinolo AA Gutkind JS Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01Clin Cancer Res2004 1040294037
Not in our library10.1158/1078-0432.ccr-03-0249
63.
Suzuki M Shinohara F Endo M Sugazaki M Echigo S Rikiishi H Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cellsCancer Chemother Pharmacol2009 64223232
Not in our library10.1007/s00280-008-0833-4
64.
Bauer K Dowejko A Bosserhoff AK Reichert TE Bauer RJ P-cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylationCarcinogenesis2009 3017811788
Not in our library10.1093/carcin/bgp175
65.
Malumbres M Barbacid M Cell cycle, CDKs and cancer: a changing paradigmNat Rev Cancer2009 9153166
Not in our library10.1038/nrc2602
66.
Sartor M Steingrimsdottir H Elamin F Gaken J Warnakulasuriya S Partridge M Thakker N Johnson NW Tavassoli M Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell linesBr J Cancer1999 807986
Not in our library10.1038/sj.bjc.6690505
67.
Turatti E da Costa Neves A de Magalhaes MH de Sousa SO Assessment of c-Jun, c-Fos and cyclin D1 in premalignant and malignant oral lesionsJ Oral Sci2005 477176
Not in our library10.2334/josnusd.47.71
68.
Mihara M Shintani S Nakahara Y Kiyota A Ueyama Y Matsumura T Wong DT Overexpression of CDK2 is a prognostic indicator of oral cancer progressionJpn J Cancer Res2001 92352360
Not in our library10.1111/j.1349-7006.2001.tb01102.x
69.
Fraczek M Wozniak Z Ramsey D Krecicki T Expression patterns of cyclin E, cyclin A and CDC25 phosphatases in laryngeal carcinogenesisEur Arch Otorhinolaryngol2007 264923928
Not in our library10.1007/s00405-007-0276-2
70.
Diehl JA Cheng M Roussel MF Sherr CJ Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localizationGenes Dev1998 1234993511
Not in our library10.1101/gad.12.22.3499
71.
Welcker M Singer J Loeb KR Grim J Bloecher A Gurien-West M Clurman BE Roberts JM Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradationMol Cell2003 12381392
Not in our library10.1016/s1097-2765(03)00287-9
72.
Leis H Segrelles C Ruiz S Santos M Paramio JM Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesisMol Carcinog2002 35180185
Not in our library10.1002/mc.10087
73.
Goto H Kawano K Kobayashi I Sakai H Yanagisawa S Expression of cyclin D1 and GSK-3beta and their predictive value of prognosis in squamous cell carcinomas of the tongueOral Oncol2002 38549556
Not in our library10.1016/s1368-8375(01)00121-x
74.
Tokumaru Y Yamashita K Osada M Nomoto S Sun DI Xiao Y Hoque MO Westra WH Califano JA Sidransky D Inverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencingCancer Res2004 6459825987
Not in our library10.1158/0008-5472.can-04-0993
75.
Yamazaki K Hasegawa M Ohoka I Hanami K Asoh A Nagao T Sugano I Ishida Y Increased E2F-1 expression via tumour cell proliferation and decreased apoptosis are correlated with adverse prognosis in patients with squamous cell carcinoma of the oesophagusJ Clin Pathol2005 58904910
Not in our library10.1136/jcp.2004.023127
76.
Meyer N Penn LZ Reflecting on 25 years with MYCNat Rev Cancer2008 8976990
Not in our library10.1038/nrc2231
77.
Miliani de Marval PL Macias E Rounbehler R Sicinski P Kiyokawa H Johnson DG Conti CJ Rodriguez-Puebla ML Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissuesMol Cell Biol2004 2475387547
Not in our library10.1128/mcb.24.17.7538-7547.2004
78.
Nadal A Jares P Pinyol M Conde L Romeu C Fernandez PL Campo E Cardesa A Association of CDK4 and CCND1 mRNA overexpression in laryngeal squamous cell carcinomas occurs without CDK4 amplificationVirchows Arch2007 450161167
Not in our library10.1007/s00428-006-0314-2
79.
Nemes JA Nemes Z Marton IJ p21WAF1/CIP1 expression is a marker of poor prognosis in oral squamous cell carcinomaJ Oral Pathol Med2005 34274279
Not in our library10.1111/j.1600-0714.2005.00310.x
80.
Yokoyama K Kamata N Fujimoto R Tsutsumi S Tomonari M Taki M Hosokawa H Nagayama M Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomasInt J Oncol2003 22891898
Not in our library
81.
Rossig L Badorff C Holzmann Y Zeiher AM Dimmeler S Glycogen synthase kinase-3 couples AKT-dependent signaling to the regulation of p21Cip1 degradationJ Biol Chem2002 27796849689
Not in our library10.1074/jbc.m106157200
82.
Kudo Y Kitajima S Ogawa I Miyauchi M Takata T Down-regulation of Cdk inhibitor p27 in oral squamous cell carcinomaOral Oncol2005 41105116
Not in our library10.1016/j.oraloncology.2004.05.003
83.
Zhou Y Uddin S Zimmerman T Kang JA Ulaszek J Wickrema A Growth control of multiple myeloma cells through inhibition of glycogen synthase kinase-3Leuk Lymphoma2008 4919451953
Not in our library10.1080/10428190802304966
84.
Reagan-Shaw S Ahmad N RNA interference-mediated depletion of phosphoinositide 3-kinase activates forkhead box class O transcription factors and induces cell cycle arrest and apoptosis in breast carcinoma cellsCancer Res2006 6610621069
Not in our library10.1158/0008-5472.can-05-1018
85.
Ying J Srivastava G Hsieh WS Gao Z Murray P Liao SK Ambinder R Tao Q The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumorsClin Cancer Res2005 1164426449
Not in our library10.1158/1078-0432.ccr-05-0267
86.
Chen JC Lu KW Tsai ML Hsu SC Kuo CL Yang JS Hsia TC Yu CS Chou ST Kao MC Gypenosides induced G0/G1 arrest via CHk2 and apoptosis through endoplasmic reticulum stress and mitochondria-dependent pathways in human tongue cancer SCC-4 cellsOral Oncol2009 45273283
Not in our library10.1016/j.oraloncology.2008.05.012
87.
Obaya AJ Mateyak MK Sedivy JM Mysterious liaisons: the relationship between c-Myc and the cell cycleOncogene1999 1829342941
Not in our library10.1038/sj.onc.1202749
88.
Kang T Wei Y Honaker Y Yamaguchi H Appella E Hung MC Piwnica-Worms H GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancersCancer Cell2008 133647
Not in our library10.1016/j.ccr.2007.12.002
89.
Rosivatz E Becker I Specht K Fricke E Luber B Busch R Hofler H Becker KF Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancerAm J Pathol2002 16118811891
Not in our library10.1016/s0002-9440(10)64464-1
90.
Yang MH Chang SY Chiou SH Liu CJ Chi CW Chen PM Teng SC Wu KJ Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancerOncogene2007 2614591467
Not in our library10.1038/sj.onc.1209929
91.
Kosmehl H Berndt A Strassburger S Borsi L Rousselle P Mandel U Hyckel P Zardi L Katenkamp D Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinomaBr J Cancer1999 8110711079
Not in our library10.1038/sj.bjc.6690809
92.
Mhawech P Dulguerov P Assaly M Ares C Allal AS EB-D fibronectin expression in squamous cell carcinoma of the head and neckOral Oncol2005 418288
Not in our library10.1016/j.oraloncology.2004.07.003
93.
de Nigris F Botti C Rossiello R Crimi E Sica V Napoli C Cooperation between Myc and YY1 provides novel silencing transcriptional targets of alpha3beta1-integrin in tumour cellsOncogene2007 26382394
Not in our library10.1038/sj.onc.1209804
94.
Haraguchi M Okubo T Miyashita Y Miyamoto Y Hayashi M Crotti TN McHugh KP Ozawa M Snail regulates cell-matrix adhesion by regulation of the expression of integrins and basement membrane proteinsJ Biol Chem2008 2832351423523
Not in our library10.1074/jbc.m801125200
95.
Erdem NF Carlson ER Gerard DA Ichiki AT Characterization of 3 oral squamous cell carcinoma cell lines with different invasion and/or metastatic potentialsJ Oral Maxillofac Surg2007 6517251733
Not in our library10.1016/j.joms.2006.11.034
96.
Ziober BL Silverman SS Jr Kramer RH Adhesive mechanisms regulating invasion and metastasis in oral cancerCrit Rev Oral Biol Med2001 12499510
Not in our library10.1177/10454411010120060401
97.
Kornberg LJ Focal adhesion kinase expression in oral cancersHead Neck1998 20634639
Not in our library10.1002/(sici)1097-0347(199810)20:7<634::aid-hed10>3.0.co;2-m
98.
Ko BS Chang TC Chen CH Liu CC Kuo CC Hsu C Shen YC Shen TL Golubovskaya VM Chang CC Bortezomib suppresses focal adhesion kinase expression via interrupting nuclear factor-kappa BLife Sci2010 86199206
Not in our library10.1016/j.lfs.2009.12.003
99.
Bianchi M De Lucchini S Marin O Turner DL Hanks SK Villa-Moruzzi E Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migrationBiochem J2005 391359370
Not in our library10.1042/bj20050282
100.
Ramos DM Dang D Sadler S The role of the integrin alpha v beta6 in regulating the epithelial to mesenchymal transition in oral cancerAnticancer Res2009 29125130
Not in our library
101.
Han S Roman J COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sitesInt J Cancer2005 116536546
Not in our library10.1002/ijc.21125
102.
Zutter MM Santoro SA Painter AS Tsung YL Gafford A The human alpha 2 integrin gene promoter. Identification of positive and negative regulatory elements important for cell-type and developmentally restricted gene expressionJ Biol Chem1994 269463469
Not in our library
103.
Nishida K Kitazawa R Mizuno K Maeda S Kitazawa S Identification of regulatory elements of human alpha 6 integrin subunit geneBiochem Biophys Res Commun1997 241258263
Not in our library10.1006/bbrc.1997.7808
104.
Corbi AL Jensen UB Watt FM The alpha2 and alpha5 integrin genes: identification of transcription factors that regulate promoter activity in epidermal keratinocytesFEBS Lett2000 474201207
Not in our library10.1016/s0014-5793(00)01591-x
105.
Barrallo-Gimeno A Nieto MA The Snail genes as inducers of cell movement and survival: implications in development and cancerDevelopment2005 13231513161
Not in our library10.1242/dev.01907
106.
Jordan RC Macabeo-Ong M Shiboski CH Dekker N Ginzinger DG Wong DT Schmidt BL Overexpression of matrix metalloproteinase-1 and -9 mRNA is associated with progression of oral dysplasia to cancerClin Cancer Res2004 1064606465
Not in our library10.1158/1078-0432.ccr-04-0656
107.
Katayama A Bandoh N Kishibe K Takahara M Ogino T Nonaka S Harabuchi Y Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosisClin Cancer Res2004 10634640
Not in our library10.1158/1078-0432.ccr-0864-02
108.
Expression of matrix metalloproteinases (MMP-1 and -2) and their inhibitors (TIMP-1, -2 and -3) in oral lichen planus, dysplasia, squamous cell carcinoma and lymph node metastasis · 1998
No notice
109.
Impola U Uitto VJ Hietanen J Hakkinen L Zhang L Larjava H Isaka K Saarialho-Kere U Differential expression of matrilysin-1 (MMP-7), 92 kD gelatinase (MMP-9), and metalloelastase (MMP-12) in oral verrucous and squamous cell cancerJ Pathol2004 2021422
Not in our library10.1002/path.1479
110.
Kinugasa Y Hatori M Ito H Kurihara Y Ito D Nagumo M Inhibition of cyclooxygenase-2 suppresses invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 and CD44Clin Exp Metastasis2004 21737745
Not in our library10.1007/s10585-005-1190-x
111.
Kosunen A Pirinen R Ropponen K Pukkila M Kellokoski J Virtaniemi J Sironen R Juhola M Kumpulainen E Johansson R CD44 expression and its relationship with MMP-9, clinicopathological factors and survival in oral squamous cell carcinomaOral Oncol2007 435159
Not in our library10.1016/j.oraloncology.2006.01.003
112.
Lee CH Liu SY Lin MH Chiang WF Chen TC Huang WT Chou DS Chiu CT Liu YC Upregulation of matrix metalloproteinase-1 (MMP-1) expression in oral carcinomas of betel quid (BQ) users: roles of BQ ingredients in the acceleration of tumour cell motility through MMP-1Arch Oral Biol2008 53810818
Not in our library10.1016/j.archoralbio.2008.05.004
113.
Yokoyama K Kamata N Hayashi E Hoteiya T Ueda N Fujimoto R Nagayama M Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitroOral Oncol2001 376571
Not in our library10.1016/s1368-8375(00)00059-2
114.
Taki M Kamata N Yokoyama K Fujimoto R Tsutsumi S Nagayama M Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cellsCancer Sci2003 94593597
Not in our library10.1111/j.1349-7006.2003.tb01488.x
115.
Schipper JH Frixen UH Behrens J Unger A Jahnke K Birchmeier W E-cadherin expression in squamous cell carcinomas of head and neck: inverse correlation with tumor dedifferentiation and lymph node metastasisCancer Res1991 5163286337
Not in our library
116.
Batlle E Sancho E Franci C Dominguez D Monfar M Baulida J Garcia De Herreros A The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cellsNat Cell Biol2000 28489
Not in our library10.1038/35000034
117.
Sappayatosok K Maneerat Y Swasdison S Viriyavejakul P Dhanuthai K Zwang J Chaisri U Expression of pro-inflammatory protein, iNOS, VEGF and COX-2 in oral squamous cell carcinoma (OSCC), relationship with angiogenesis and their clinico-pathological correlationMed Oral Patol Oral Cir Bucal2009 14E319324
Not in our library
118.
Nystrom ML McCulloch D Weinreb PH Violette SM Speight PM Marshall JF Hart IR Thomas GJ Cyclooxygenase-2 inhibition suppresses alphavbeta6 integrin-dependent oral squamous carcinoma invasionCancer Res2006 661083310842
Not in our library10.1158/0008-5472.can-06-1640
119.
Kurihara Y Hatori M Ando Y Ito D Toyoshima T Tanaka M Shintani S Inhibition of cyclooxygenase-2 suppresses the invasiveness of oral squamous cell carcinoma cell lines via down-regulation of matrix metalloproteinase-2 production and activationClin Exp Metastasis2009 26425432
Not in our library10.1007/s10585-009-9241-3
120.
Subbaramaiah K Altorki N Chung WJ Mestre JR Sampat A Dannenberg AJ Inhibition of cyclooxygenase-2 gene expression by p53J Biol Chem1999 2741091110915
Not in our library10.1074/jbc.274.16.10911
121.
Chiang SL Chen PH Lee CH Ko AM Lee KW Lin YC Ho PS Tu HP Wu DC Shieh TY Ko YC Up-regulation of inflammatory signalings by areca nut extract and role of cyclooxygenase-2 -1195G > a polymorphism reveal risk of oral cancerCancer Res2008 6884898498
Not in our library10.1158/0008-5472.can-08-0823
122.
Tamatani T Azuma M Ashida Y Motegi K Takashima R Harada K Kawaguchi S Sato M Enhanced radiosensitization and chemosensitization in NF-kappaB-suppressed human oral cancer cells via the inhibition of gamma-irradiation- and 5-FU-induced production of IL-6 and IL-8Int J Cancer2004 108912921
Not in our library10.1002/ijc.11640
123.
Beurel E Jope RS The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathwaysProg Neurobiol2006 79173189
Not in our library10.1016/j.pneurobio.2006.07.006
124.
Hoeflich KP Luo J Rubie EA Tsao MS Jin O Woodgett JR Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activationNature2000 4068690
Not in our library10.1038/35017574
125.
Tan J Zhuang L Leong HS Iyer NG Liu ET Yu Q Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cellsCancer Res2005 6590129020
Not in our library10.1158/0008-5472.can-05-1226
126.
Lonze BE Ginty DD Function and regulation of CREB family transcription factors in the nervous systemNeuron2002 35605623
Not in our library10.1016/s0896-6273(02)00828-0
127.
Uchida M Iwase M Takaoka S Yoshiba S Kondo G Watanabe H Ohashi M Nagumo M Shintani S Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitorsInt J Oncol2007 3011631171
Not in our library
128.
Belkhiri A Dar AA Zaika A Kelley M El-Rifai W t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanismCancer Res2008 68395403
Not in our library10.1158/0008-5472.can-07-1580
129.
Ballou LM Tian PY Lin HY Jiang YP Lin RZ Dual regulation of glycogen synthase kinase-3beta by the alpha1A-adrenergic receptorJ Biol Chem2001 2764091040916
Not in our library10.1074/jbc.m103480200
130.
Tanji C Yamamoto H Yorioka N Kohno N Kikuchi K Kikuchi A A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta) and mediates protein kinase A-dependent inhibition of GSK-3betaJ Biol Chem2002 2773695536961
Not in our library10.1074/jbc.m206210200
131.
Arun P Brown MS Ehsanian R Chen Z Van Waes C Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancerClin Cancer Res2009 1559745984
Not in our library10.1158/1078-0432.ccr-09-1352
132.
Tosi L Rinaldi E Carinci F Farina A Pastore A Pelucchi S Cassano L Evangelisti R Carinci P Volinia S Akt, protein kinase C, and mitogen-activated protein kinase phosphorylation status in head and neck squamous cell carcinomaHead Neck2005 27130137
Not in our library10.1002/hed.20120
133.
Moral M Paramio JM Akt pathway as a target for therapeutic intervention in HNSCCHistol Histopathol2008 2312691278
Not in our library10.14670/hh-23.1269
134.
Tsai CH Hsieh YS Yang SF Chou MY Chang YC Matrix metalloproteinase 2 and matrix metalloproteinase 9 expression in human oral squamous cell carcinoma and the effect of protein kinase C inhibitors: preliminary observationsOral Surg Oral Med Oral Pathol Oral Radiol Endod2003 95710716
Not in our library10.1067/moe.2003.121
135.
Pan Q Bao LW Teknos TN Merajver SD Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinomaCancer Res2006 6693799384
Not in our library10.1158/0008-5472.can-06-2646
136.
Doehn U Hauge C Frank SR Jensen CJ Duda K Nielsen JV Cohen MS Johansen JV Winther BR Lund LR RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cellsMol Cell2009 35511522
Not in our library10.1016/j.molcel.2009.08.002
137.
Sheu JJ Hua CH Wan L Lin YJ Lai MT Tseng HC Jinawath N Tsai MH Chang NW Lin CF Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinomaCancer Res2009 6925682576
Not in our library10.1158/0008-5472.can-08-3199
138.
Saito Y Vandenheede JR Cohen P The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cellsBiochem J1994 303Pt 12731
Not in our library10.1042/bj3030027
139.
Amornphimoltham P Patel V Sodhi A Nikitakis NG Sauk JJ Sausville EA Molinolo AA Gutkind JS Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neckCancer Res2005 6599539961
Not in our library10.1158/0008-5472.can-05-0921
140.
West KA Brognard J Clark AS Linnoila IR Yang X Swain SM Harris C Belinsky S Dennis PA Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cellsJ Clin Invest2003 1118190
Not in our library10.1172/jci16147
141.
Hope BT Nagarkar D Leonard S Wise RA Long-term upregulation of protein kinase A and adenylate cyclase levels in human smokersJ Neurosci2007 2719641972
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142.
Du B Altorki NK Kopelovich L Subbaramaiah K Dannenberg AJ Tobacco smoke stimulates the transcription of amphiregulin in human oral epithelial cells: evidence of a cyclic AMP-responsive element binding protein-dependent mechanismCancer Res2005 6559825988
Not in our library10.1158/0008-5472.can-05-0628
143.
Hecht SS Cigarette smoking and lung cancer: chemical mechanisms and approaches to preventionLancet Oncol2002 3461469
Not in our library10.1016/s1470-2045(02)00815-x
144.
Nakayama H Numakawa T Ikeuchi T Nicotine-induced phosphorylation of Akt through epidermal growth factor receptor and Src in PC12h cellsJ Neurochem2002 8313721379
Not in our library10.1046/j.1471-4159.2002.01248.x
145.
Sugano N Minegishi T Kawamoto K Ito K Nicotine inhibits UV-induced activation of the apoptotic pathwayToxicol Lett2001 1256165
Not in our library10.1016/s0378-4274(01)00416-7
146.
Etique N Flament S Lecomte J Grillier-Vuissoz I Ethanol-induced ligand-independent activation of ERalpha mediated by cyclic AMP/PKA signaling pathway: an in vitro study on MCF-7 breast cancer cellsInt J Oncol2007 3115091518
Not in our library
147.
Pim D Massimi P Dilworth SM Banks L Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2AOncogene2005 2478307838
Not in our library10.1038/sj.onc.1208935
148.
Perez-Plasencia C Vazquez-Ortiz G Lopez-Romero R Pina-Sanchez P Moreno J Salcedo M Genome wide expression analysis in HPV16 Cervical Cancer: identification of altered metabolic pathwaysInfect Agent Cancer2007 216
Not in our library10.1186/1750-9378-2-16
149.
Sun Y p53 and its downstream proteins as molecular targets of cancerMol Carcinog2006 45409415
Not in our library10.1002/mc.20231
150.
Matsuda T Zhai P Maejima Y Hong C Gao S Tian B Goto K Takagi H Tamamori-Adachi M Kitajima S Sadoshima J Distinct roles of GSK-3alpha and GSK-3beta phosphorylation in the heart under pressure overloadProc Natl Acad Sci USA2008 1052090020905
Not in our library10.1073/pnas.0808315106
151.
Yang J Cron P Good VM Thompson V Hemmings BA Barford D Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNPNat Struct Biol2002 9940944
Not in our library10.1038/nsb870
152.
Dajani R Fraser E Roe SM Yeo M Good VM Thompson V Dale TC Pearl LH Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complexEMBO J2003 22494501
Not in our library10.1093/emboj/cdg068
153.
Bax B Carter PS Lewis C Guy AR Bridges A Tanner R Pettman G Mannix C Culbert AA Brown MJ The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylationStructure2001 911431152
Not in our library10.1016/s0969-2126(01)00679-7
154.
Dajani R Fraser E Roe SM Young N Good V Dale TC Pearl LH Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibitionCell2001 105721732
Not in our library10.1016/s0092-8674(01)00374-9
155.
Clayman GL el-Naggar AK Lippman SM Henderson YC Frederick M Merritt JA Zumstein LA Timmons TM Liu TJ Ginsberg L Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinomaJ Clin Oncol1998 1622212232
Not in our library10.1200/jco.1998.16.6.2221
156.
Cao Q Lu X Feng YJ Glycogen synthase kinase-3beta positively regulates the proliferation of human ovarian cancer cellsCell Res2006 16671677
Not in our library10.1038/sj.cr.7310078
157.
Sun A Shanmugam I Song J Terranova PF Thrasher JB Li B Lithium suppresses cell proliferation by interrupting E2F-DNA interaction and subsequently reducing S-phase gene expression in prostate cancerProstate2007 67976988
Not in our library10.1002/pros.20586
158.
Ghosh JC Altieri DC Activation of p53-dependent apoptosis by acute ablation of glycogen synthase kinase-3beta in colorectal cancer cellsClin Cancer Res2005 1145804588
Not in our library10.1158/1078-0432.ccr-04-2624
159.
Shakoori A Mai W Miyashita K Yasumoto K Takahashi Y Ooi A Kawakami K Minamoto T Inhibition of GSK-3 beta activity attenuates proliferation of human colon cancer cells in rodentsCancer Sci2007 9813881393
Not in our library10.1111/j.1349-7006.2007.00545.x
160.
Jordan CT The leukemic stem cellBest Pract Res Clin Haematol2007 201318
Not in our library10.1016/j.beha.2006.10.005
161.
Ougolkov AV Fernandez-Zapico ME Bilim VN Smyrk TC Chari ST Billadeau DD Aberrant nuclear accumulation of glycogen synthase kinase-3beta in human pancreatic cancer: association with kinase activity and tumor dedifferentiationClin Cancer Res2006 1250745081
Not in our library10.1158/1078-0432.ccr-06-0196
162.
Garcea G Manson MM Neal CP Pattenden CJ Sutton CD Dennison AR Berry DP Glycogen synthase kinase-3 beta; a new target in pancreatic cancer?Curr Cancer Drug Targets2007 7209215
Not in our library10.2174/156800907780618266
163.
Mamaghani S Patel S Hedley DW Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapyBMC Cancer2009 9132
Not in our library10.1186/1471-2407-9-132
164.
Zhou H Tang Y Liang X Yang X Yang J Zhu G Zheng M Zhang C RNAi targeting urokinase-type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivoInt J Cancer2009 125453462
Not in our library10.1002/ijc.24360
165.
Lage H Therapeutic potential of RNA interference in drug-resistant cancersFuture Oncol2009 5169185
Not in our library10.2217/14796694.5.2.169
166.
Mai W Kawakami K Shakoori A Kyo S Miyashita K Yokoi K Jin M Shimasaki T Motoo Y Minamoto T Deregulated GSK3{beta} sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomeraseClin Cancer Res2009 1568106819
Not in our library10.1158/1078-0432.ccr-09-0973
167.
Weinstein IB Cancer. Addiction to oncogenes--the Achilles heal of cancerScience2002 2976364
Not in our library10.1126/science.1073096
168.
Ding Q He X Xia W Hsu JM Chen CT Li LY Lee DF Yang JY Xie X Liu JC Hung MC Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancerCancer Res2007 6745644571
Not in our library10.1158/0008-5472.can-06-1788
169.
Farago M Dominguez I Landesman-Bollag E Xu X Rosner A Cardiff RD Seldin DC Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesisCancer Res2005 6557925801
Not in our library10.1158/0008-5472.can-05-1021
170.
Dong J Peng J Zhang H Mondesire WH Jian W Mills GB Hung MC Meric-Bernstam F Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivityCancer Res2005 6519611972
Not in our library10.1158/0008-5472.can-04-2501
171.
Dal Col J Dolcetti R GSK-3beta inhibition: at the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphomaCell Cycle2008 728132816
Not in our library10.4161/cc.7.18.6733
172.
Wang Y Lam JB Lam KS Liu J Lam MC Hoo RL Wu D Cooper GJ Xu A Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude miceCancer Res2006 661146211470
Not in our library10.1158/0008-5472.can-06-1969
173.
Morrison JA Gulley ML Pathmanathan R Raab-Traub N Differential signaling pathways are activated in the Epstein-Barr virus-associated malignancies nasopharyngeal carcinoma and Hodgkin lymphomaCancer Res2004 6452515260
Not in our library10.1158/0008-5472.can-04-0538
174.
Zheng H Saito H Masuda S Yang X Takano Y Phosphorylated GSK3beta-ser9 and EGFR are good prognostic factors for lung carcinomasAnticancer Res2007 2735613569
Not in our library
175.
Mai W Miyashita K Shakoori A Zhang B Yu ZW Takahashi Y Motoo Y Kawakami K Minamoto T Detection of active fraction of glycogen synthase kinase 3beta in cancer cells by nonradioisotopic in vitro kinase assayOncology2006 71297305
Not in our library10.1159/000106429
176.
Ougolkov AV Fernandez-Zapico ME Savoy DN Urrutia RA Billadeau DD Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cellsCancer Res2005 6520762081
Not in our library10.1158/0008-5472.can-04-3642
177.
Ougolkov AV Billadeau DD Targeting GSK-3: a promising approach for cancer therapy?Future Oncol2006 291100
Not in our library10.2217/14796694.2.1.91
178.
Bilim V Ougolkov A Yuuki K Naito S Kawazoe H Muto A Oya M Billadeau D Motoyama T Tomita Y Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinomaBr J Cancer2009 10120052014
Not in our library10.1038/sj.bjc.6605437
179.
Abrahamsson AE Geron I Gotlib J Dao KH Barroga CF Newton IG Giles FJ Durocher J Creusot RS Karimi M Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generationProc Natl Acad Sci USA2009 10639253929
Not in our library10.1073/pnas.0900189106
180.
Ougolkov AV Bone ND Fernandez-Zapico ME Kay NE Billadeau DD Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cellsBlood2007 110735742
Not in our library10.1182/blood-2006-12-060947
181.
Wang Z Smith KS Murphy M Piloto O Somervaille TC Cleary ML Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapyNature2008 45512051209
Not in our library10.1038/nature07284
182.
Adler JT Cook M Luo Y Pitt SC Ju J Li W Shen B Kunnimalaiyaan M Chen H Tautomycetin and tautomycin suppress the growth of medullary thyroid cancer cells via inhibition of glycogen synthase kinase-3betaMol Cancer Ther2009 8914920
Not in our library10.1158/1535-7163.mct-08-0712
183.
Kotliarova S Pastorino S Kovell LC Kotliarov Y Song H Zhang W Bailey R Maric D Zenklusen JC Lee J Fine HA Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulationCancer Res2008 6866436651
Not in our library10.1158/0008-5472.can-08-0850

Cited by papers we hold 2

Genetics, diagnosis and management of colorectal cancer (Review) · 2015
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GSK-3 as potential target for therapeutic intervention in cancer · 2014
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