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The independence of and associations among apoptosis, autophagy, and necrosis

Qi Chen, Jian Kang, Caiyun Fu

Signal Transduction and Targeted Therapy · 2018 · CC BY

doi:10.1038/s41392-018-0018-5

Abstract

Cell death is an essential biological process for physiological growth and development. Three classical forms of cell death—apoptosis, autophagy, and necrosis—display distinct morphological features by activating specific signaling pathways. With recent research advances, we have started to appreciate that these cell death processes can cross-talk through interconnecting, even overlapping, signaling pathways, and the final cell fate is the result of the interplay of different cell death programs. This review provides an insight into the independence of and associations among these three types of cell death and explores the significance of cell death under the specific conditions of human diseases, particularly neurodegenerative diseases and cancer.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

For unicellular organisms, cell death is the end of life. However, for multicellular organisms, cell death is an essential biological process for physiological growth and development. Deregulation of cell death is involved in the pathogenesis of a wide range of human diseases, such as neurodegenerative diseases and cancer. Three classical forms of cell death—apoptosis, autophagy, and necrosis—display distinct morphological features by activating specific signaling pathways. In brief, apoptosis is a caspase-mediated programmed cell death, that is characterized by chromosome condensation, nuclear fragmentation, and membrane blebbing. In contrast to apoptosis, necrosis is considered to be an unregulated, accidental cell death caused by nonspecific, or non-physiological stress inducers and is characterized by the expansion of cellular organelles, plasma membrane rupture, and subsequent inflammatory responses caused by release of the intracellular contents,. The third form of cell death, autophagy, is accompanied by the formation of the autophagosome, which is a bilayer vesicle containing damaged organelles, proteins, and other cytoplasmic components. The autophagosomes fuse with the lysosomes, degrading cellular macromolecules and organelles and producing renewable energy and metabolites for cells. Autophagy acts as a pro-survival mechanism but can also induce autophagic cell death, which is currently an active research area in cell death,. Our understanding has been rapidly expanded in the last decades owing to the great advances in cell death research. Identification of the programmed forms of necrosis has changed our perception about necrosis. More importantly, we have started to appreciate that the molecular mechanisms of various types of cell death are distinct but also overlapping. There are multiple signaling pathways independently controlling different types of cell death. However, they are interconnected, can be activated simultaneously, and can operate in parallel in cells in response to stress.

Necrosis and apoptosis are two types of cell death with different mechanisms,. Autophagy can be described as a degradation mechanism rather than as a form of cell death, although it can also induce cell death. Of the cell death types, autophagy has the highest survival superiority, followed by apoptosis, with necrosis having the lowest survival superiority. Autophagy is instinctively induced prior to apoptosis when cells are stimulated by stress, and apoptosis rather than necrosis is induced if autophagy is inhibited or ineffective,–. Thus, two or three types of cell death may be induced simultaneously or successively when cells are exposed to certain stimuli. If the three types of cell death are placed on an axis according to their survival superiority, autophagy, and necrosis would be placed at opposing ends, whereas apoptosis would be placed in the middle; furthermore, programmed necrosis would be placed between necrosis and apoptosis (Fig. 1).

Herein, we review the different types of cell death, discuss the specific mechanisms involved in each type of cell death and connections among them, and explore the impact of different types of cell death on disease treatment.

Apoptosis

Apoptosis is generally considered a caspase-mediated programmed cell death,,,. Apoptotic cells display distinct morphological characteristics, including cell shrinkage, chromosome condensation, nuclear fragmentation (late stage), plasma membrane blebbing and the formation of apoptotic bodies, and exhibit biochemical changes, such as the exposure of phosphatidyl-l-serine on the outer plasma membrane (early stage)–. Apoptosis can be activated via either the death receptor-mediated apoptosis pathway, the mitochondria-dependent apoptosis pathway or endoplasmic reticulum (ER) stress-induced apoptosis pathways (Fig. 2).

The death receptor-mediated apoptosis pathway is activated upon the binding of the Fas ligand, TNF-α (tumor necrosis factor α), or TRAIL to the corresponding death receptors,. The adaptor protein FADD, and the procaspase-8 protein form a complex, namely, death-inducing signaling complex (DISC). In DISC, procaspase-8 is activated by autohydrolysis. The activated caspase-8 transduces the apoptosis signal through either the activation of caspase-3 or cleavage of Bid to truncated Bid (tBid). tBid translocates to the mitochondria, resulting in conformational changes in Bax and Bak and their oligomerization for pore formation in the outer mitochondrial membrane,.

The mitochondrial-dependent pathway can be activated by various stress inducers such as DNA damage, growth factor withdrawal, and oxidative stress,. The Bcl-2 family of proteins controls this intrinsic pathway by regulating the permeability of the mitochondrial outer membrane–. Upon release from the mitochondria into the cytoplasm, cytochrome c combines with Apaf-1 to promote caspase-9 activation, which, in turn, activates effector caspases, to trigger a cascade of proteolytic events.

In addition, ER stresses, such as calcium homeostasis disturbance, excessive unfolded, or misfolded protein accumulation in the ER, nutrient deprivation, and hypoxia, can induce apoptosis. This apoptosis is mediated by caspase-12, an ER-resistant caspase. Activated caspase-12 directly cleaves caspase-9 after translocation from the ER into the cytosol, followed by caspase-3 activation. The molecular mechanisms of activation of caspase-12 during ER stress include forming a complex with the inositol-requiring enzyme-1α-TNF receptor-associated factor 2 (TRAF2) complex, or by calpains, a family of Ca2+-dependent intracellular cysteine proteases.

Autophagy

Autophagy is a self-degradative process in response to various stresses, including nutrient deficiency, organelle damage, hypoxia, reactive oxygen species (ROS), ER stress, and drug treatment. The process of autophagy involves four key steps—initiation, nucleation, fusion of autophagosome and lysosome, and hydrolyzation. Our understanding of the molecular mechanisms of autophagy starts from research in yeast. A set of autophagy regulatory molecules was identified by genetic screening in yeast, particularly autophagy (Atg)-related proteins, which are the main players in autophagy. The assembly and aggregation of the Atg1 complex, which includes Atg1, Atg13, Atg17, Atg29, and Atg31,, are required for the formation of the phagophore at the initiation step. However, in mammals, the UNC-51-like kinase 1 (ULK)-mAtg13-FIP200 complex, comprising the homologous analogs to yeast Atg1, Atg13, and Atg17, is formed. At the step of nucleation, phagophore formation at the ER and other membranes is controlled by a complex of the class III PI-3 kinase VPS34, Atg6 (known as Beclin1 in mammals), Atg14, and Vps15. Atg9 and vesicle membrane protein VMP1, which circulate in the Golgi complex, autophagosomes, and endosomes, may be involved in the transport of lipids to the isolation membrane,. The expansion and closure of the autophagosome require two ubiquitin-like protein-conjugated systems, namely, Atg12 and Atg8 (Atg8 is also known as LC3 in mammals). The Atg12 system includes five Atg proteins, Atg5, Atg7, Atg10, Atg12, and Atg16–. Atg12 is activated by Atg7, which is an E1-like enzyme, and is then transferred to the E2-like enzyme Atg10. Finally, the C-terminal glycine of Atg12 covalently binds to the Lys149 side chain of Atg5 before binding to the dimer protein Atg16 to form the E3-like complex. The Atg8 system including four Atg proteins, Atg3, Atg4, Atg7, and Atg8, represents another ubiquitin-like protein-conjugated system. Atg8 is cleaved by Atg4, a cysteine protease, and exposes its C-terminal glycine residue (LC3 I in mammals). Atg8 is further activated by Atg7, an E1-like enzyme and is then transferred to Atg3, an E2-like enzyme, before covalently binding to the amidogen of PE through the E3-like Atg12-Atg5-Atg16 complex,. The Atg8-PE covalent structure (LC3 II in mammals) confers Atg8 membrane tethering and hemifusion ability and plays a critical role in autophagosome formation. LC3 II is associated with both the outer and inner membranes of the autophagosome and is a typical marker of autophagy formation. The Atg8-PE covalent structure can be reversibly cleaved to Atg8 by Atg4 for the recycling of Atg8. Subsequently, the fusion of autophagosome and lysosome is mediated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-like proteins–. Finally, at a low pH, various lysosomal enzymes hydrolyze all types of damaged organelles, proteins, lipids, and nucleic acids,. A diagram of the autophagy process is shown in Fig. 3.

Necrosis and necroptosis

Unlike apoptosis, necrosis is often considered to be an unregulated and accidental cell death. However, the identification of programmed necrosis supported the existence of multiple nonapoptotic regulated cell death mechanisms. Several types of programmed necrosis have been reported, including necroptosis, parthanatos, ferroptosis, pyroptosis, and NETosis. Here, we focus on necroptosis, a type of regulated necrotic cell death that shares several key signaling pathways with apoptosis. Most of the knowledge regarding necroptosis originated from investigations of TNF signaling. TNF is a pleiotropic cytokine that plays an important role in the process of inflammation. TNF is also a potent cell death inducer under certain conditions through binding to TNFR. Although an early study revealed that TNF-induced RIPK1-mediated caspase-independent cell death, TNF-induced nonapoptotic cell death did not attract much attention, until researchers further uncovered that cells executed necrosis-like death when apoptosis was blocked,.

Necroptosis is initiated by the engagement of death receptors, such as TNFR1– and Toll-like receptors (TLRs)–. TNF binding to the death receptor TNFR induces the conformational changes of TNFR, which recruits multiple proteins, including TNFR1-associated death domain protein (TRADD), RIPK1, TRAF2, E3 ubiquitin ligases, cIAP1/2, and LUBAC, to form TRADD and the RIPK1-dependent complex I. This multi-protein complex transduces pro-inflammatory and pro-survival signals by recruiting TGF-activated kinase 1 (TAK1)-binding protein (TAB) complexes and Iκb kinase (IKK) complexes consisting of IKK1, IKK2, and NF-κB essential modulator (NEMO), to activate NF-κB signaling, AP-1 signaling, and mitogen-activated protein kinase signaling. When RIPK1 is deubiquitinated by cylindromatosis lysine 63 deubiquitinase, complex I becomes unstable and renders the dissociation of RIPK1 and the formation of another complex, termed complex IIa, by interacting with TRADD, FADD, pro-caspase-8, and FLIP. Pro-caspase-8, together with FLIPL, cleaves RIPK1 to prevent necroptosis and activate apoptosis signaling,,. TNF–TNFR signaling can also induce apoptosis through the formation of complex IIb when the function of IAP (inhibitors of apoptosis), TAK1, NEMO, and/or Pellino3 is blocked. This complex IIb comprises RIPK1, RIPK3, FADD, pro-caspase-8, and FLIPL and causes RIPK1-dependent apoptosis. However, complex IIb may be further transformed into the necrosome, a microfilament-like complex, when the levels of RIPK3 and mixed lineage kinase domain-like (MLKL) are sufficiently high and the activity of caspase-8 is inhibited. Oligomerization and phosphorylation of RIPK3 in the necrosome lead to the recruitment and phosphorylation of MLKL,, and then MLKL translocates to the plasma membrane and causes membrane damage and necroptosis. In addition, the necrosome interacts with mitochondrial serine/threonine protein phosphatase PGAM family member 5 on the mitochondrial membrane and activates mitochondrial fission factor dynamin-related protein 1 to induce necroptosis through mitochondrial fragmentation. As mentioned above, the binding of FasL or TRAIL to the death receptor Fas or TRAILR induces the formation of DISC, activates caspase-8, and executes apoptosis. However, in the absence of cIAPs or inhibition of caspase-8, RIPK1 translocates to the membrane and promotes the formation of complex II-b and initiation of necroptosis when Fas/TRAILR is activated,,,.

Activation of TLRs induces the formation of a platform that recruits the cytoplasmic adaptor protein TRIF (Toll/IL-1 receptor domain-containing adaptor protein inducing interferon-Β). TRIF is involved in the activation of NF-κB signaling and induction of type I IFNs. By relying on its RHIM (RIP homotypic interaction motif) domain, TRIF can interact with RIPK1 and RIPK3. In the presence of the apoptosis inhibitor zVAD-fmk, activation of TLR4 by lipopolysaccharide or activation of TLR3 by polyinosine–polycytidylic acid can induce TRIF-mediated necroptosis,, which can be blocked by the inhibition of necrostatin-1 (Nec1) or knockout of RIPK1. These results suggest that the RIPK1-TRIF signaling complex plays an important role in TLR3/4-induced necroptosis. In the absence of RIPK1, TRIF can also induce necroptosis by directly recruiting and activating RIPK3,.

In addition to death receptor signaling and TLR signaling, DNA-dependent activator of IFN-regulatory factors (DAI), a cytoplasmic viral DNA sensor,, can also induce necroptosis. Like TRIF, DAI has the RHIM structure. In response to viral (such as murine cytomegalovirus) double-stranded DNA, DAI can activate NF-κB, induce type I IFNs, and mediate RIPK3-dependent necroptosis. Moreover, Wei et al. recently reported a novel necrosis mechanism, indicating that the acute cell necrosis induced by cationic nanocarriers occurs through the impairment of Na+/K+-ATPase, which causes a subsequent inflammatory response. A diagram of the process of classical necroptosis is shown in Fig. 4.

Association between apoptosis and necroptosis

Apoptosis and necroptosis may occur simultaneously or mutually transform because of the interconnection of the downstream death signaling pathways. For example, cells can commit to necrotic cell death when apoptosis is blocked, and oxidative stress-induced necrotic cell death involves the activation of the apoptosis-associated caspase-8/Bid pathway. The final form of cell death will depend on the cell type, cell microenvironment, and initial inducers.

Caspase-8 and RIPK1/3

As an apoptotic initiator caspase, caspase-8 interacts with FADD to form DISC, followed by homologous dimerization and proteolytic processing. Activated caspase-8 is then released from DISC and triggers downstream apoptotic signaling. Meanwhile, caspase-8 can inhibit necroptosis by cleaving and inactivating RIPK1 and RIPK3,,. However, when the activity of caspase-8 is inhibited pharmacologically, such as by the pan-caspase inhibitor ZVAD, or genetically, such as in RNAi-mediated knockdown, RIPK1 and RIPK3 become activated through phosphorylation and induce the formation of the necrosome to trigger necroptosis,,.

ATP

ATP plays a crucial role in the decision of cell death fate. A high level of intracellular ATP often favors apoptosis, whereas a low level often promotes necrosis. Therefore, excessive consumption of intracellular ATP or the inhibition of ATP synthesis may convert apoptosis to necrosis,. For example, substantial DNA damage leads to the activation of poly ADP-ribose polymerase-1 (PARP-1), a nuclear enzyme involved in DNA repair, resulting in the consumption of many NAD+ and ATP molecules and subsequent necrotic death,. The mitochondria is the major site that generates ATP; therefore, mitochondria dysfunction can trigger necrosis by ATP depletion. In addition, excessive mitochondrial ROS formation and the onset of the mitochondrial permeability transition are also causally linked to the conversion of apoptosis to necroptosis.

Association between autophagy and apoptosis

Autophagy is an intracellular catabolic mechanism that involves the degradation and recycling of cytoplasmic undesired components, such as malfunctioning proteins or damaged organelles, to maintain cellular homeostasis–. Autophagy is a double-edged sword and can either protect cells from apoptosis or promote apoptosis depending on the cell type, intracellular metabolic activity, extracellular nutrient supply and triggering stimuli.

Beclin1

Mammalian Beclin1 (Atg6 in yeast) cross-regulates autophagy and apoptosis through direct interaction with anti-apoptosis family members–. Beclin1 is a key molecule involved in the autophagosome formation. Beclin1 interacts with class III type PI3KC3/Vps34 and promotes the formation of the Beclin1-Vps34-Vps15 core complex,. Beclin1 is also a member of the BH3-only protein family. The antiapoptotic protein Bcl-2 or Bcl-xL combines with Beclin1 through the BH3 domains to simultaneously block the process of autophagy by inhibiting Beclin1 activity and the occurrence of endogenous apoptosis,,,. On the other hand, NOXA and other BH3-only family proteins can displace Bcl-2 family members from Beclin1 and promote autophagic cell death,. Furthermore, Beclin1 can also be cleaved by several caspase proteins, such as caspase-8 and caspase-3, to shift the cell fate from autophagy to apoptosis,. The C-terminal fragment of Beclin1 can then translocate to the mitochondria and induce mitochondrial membrane permeability and apoptosis.

Association between autophagy and necroptosis

The interconnection between autophagy and necroptosis has been investigated in several studies with conflicting results. As a protective mechanism, autophagy can unsurprisingly inhibit necroptosis,. Interestingly, autophagy appears to facilitate necroptosis in certain instances. Khan et al. reported that palmitic acid triggers Ca2+-dependent autophagy, resulting in the necroptosis of endothelial cells.

mTORC1

mTORC1 is a key sensor of nutrients, growth factors, and stress and controls cell metabolism, growth, and survival. Activation of mTORC1 by growth factors and nutrients can suppress autophagy by phosphorylation of autophagy-related proteins involved in autophagy initiation, such as ULK1 and ATG13, in the ULK complex and ATG14 in the VPS34 complex. Cellular metabolic and energetic status regulates mTORC1 activity and consequently impacts autophagy induction. At a low-energy status, AMPK signaling is activated in response to an increased AMP/ATP ratio, which inhibits the mTORC1 signaling pathway via the phosphorylation of TSC2 (tuberous sclerosis complex 2), a mTORC1 negative regulator,,–, subsequently promoting autophagy,,. Autophagy stimulation by the downregulation of mTORC1 signaling protect cells from programmed cell death, including apoptosis and necroptosis, under nutrient- or energy-deprived conditions–. As mentioned above, the activation of PARP-1 in the DNA damage response causes necrosis owing to ATP depletion, which also leads to AMPK activation, mTORC1 inhibition, and autophagy induction as the last protective resort. The balance between autophagy and necrosis will determine the cell death fate.

Cellular FILCE-like inhibitory protein (cFLIP)

FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory proteins (FLIPs) possess caspase-8-like structures but lack proteolytic activity. cFLIP has three major isoforms in humans containing one long protein cFLIPL and two short proteins cFLIPs and cFLIPR–. cFLIPL possesses a C-terminal caspase-8-like domain but does not have enzymatic activity due to the substitution of several catalytically important amino-acid residues–, whereas the other isoforms cFLIPs and cFLIPR do not possess the caspase-like C-terminal domain. Nevertheless, these three isoforms all contain two death receptor domains at the N-termini, which allow them to interact with the adaptor protein FADD to form the DISC complex.

cFLIP regulates not only the death receptor-mediated extrinsic apoptosis pathway but also death receptor-independent apoptosis pathways. In complex IIb/ripoptosome, homodimeric caspase-8 initiates apoptosis by cleaving RIPK1 and disassembling complex IIb/ripoptosome. When procaspase-8 forms a heterodimer with cFLIPL, not only is necroptosis prevented due to cleavage of RIPK1 but apoptosis is also blocked because activated caspase-8 is not formed. However, formation of a heterodimer by procaspase-8 with cFLIPS/R triggers necroptosis owing to the lack of proteolytic cleavage of RIPK1– and simultaneously fails to induce caspase-8-dependent apoptosis. Therefore, the existence of cFLIP isoforms in the ripoptosome determines whether cells will execute RIPK1-dependent necroptosis or caspase-8-dependent apoptosis.

In addition to the regulation of apoptosis and necroptosis, cFLIP is known to be a negative regulator of autophagy. During autophagosome formation, Atg3 covalently binds the microtubule-associated protein LC3. Strikingly, cFLIP prevents the combination of Atg3 and LC3 by competitively binding Atg3 and consequently inhibiting autophagy. The process in which cFLIP regulates apoptosis and necroptosis through formation of the ripoptosome occurs at the plasma membrane, but cFLIP inhibits autophagy at the sites where autophagosomes form. Thus, the different subcellular localizations of cFLIP may be important for its actions. The complex associations among the three types of cell death are summarized in Fig. 5.

Cell death in neurodegenerative diseases

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, involve the loss of structures and functions of nerve cells owing to the accumulation of abnormal proteins in the intracellular and extracellular spaces. Deregulated cell death has been implicated as a major mechanism in these neurodegenerative diseases. The intervention of cell death pathways is therefore considered a potential therapeutic strategy.

The interaction between β-amyloid accumulation and the death of neurocytes contributes to the progression of Alzheimer’s disease. β-amyloid accumulates in mitochondria, mediates mitochondrial toxicity, and induces caspase-3-dependent apoptosis, which, in turn, accelerates the formation of β-amyloid and neurofibrillary tangles. Activation of caspases also cleaves autophagy-related proteins, such as Beclin1, consequently inhibiting autophagy.

An overwhelming body of evidence indicates that the inhibition of programmed cell death may be an effective strategy for the treatment of neurodegenerative diseases. For example, the efficacy of minocycline in the treatment of Alzheimer’s disease and Parkinson’s disease has been linked to its anti-apoptosis action by inhibiting oxidative stress, cytochrome c release, and caspase-3 activation and by increasing the expression levels of anti-apoptotic proteins, such as Bcl-2. Blocking necroptosis by the RIPK1 inhibitor Nec-1 protects cortical neuronal cells of embryonic rats and mouse hippocampal neurons from excitatory toxicosis-induced cell death,. Nec-1 can also reduce the death of striatal neurons with Huntingtin (HTT) mutations and retard the process of Huntington’s disease in HTT-mutant transgenic mice. As a cell survival mechanism, promoting autophagy, by mTOR inhibitors, such as rapamycin and its analogs (CCI-779, RAD001, and AP23573), protects cells from apoptotic and necrotic cell death, and has been proven to be effective in the treatment of neurodegenerative diseases.

Cell death in cancer

A delicate balance between cell death and survival maintains the homeostasis within a cell, a tissue, and an organism. Uncontrolled cell proliferation and escape from cell death have been recognized as the hallmarks of cancer cells.

Substantial studies have suggested that autophagy plays a dual role in tumorigenesis. At the early stage, autophagy exerts an antitumor effect and curbs chronic tissue damage, inflammation, and genome instability; however, during the late stage, autophagy meets the energy and nutrient requirements to sustain tumor development. Therefore, autophagy inhibitors, such as chloroquine or hydroxychloroquine, have a therapeutic potential in cancer treatment–. Autophagy also contributes to the resistance to cancer therapy. For example, autophagy plays a protective role against quercetin or histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid)-induced apoptosis, and the combination of autophagy inhibitors and quercetin or SAHA may provide a rational utility of these drugs in the clinic,. Similarly, inhibition of autophagy has been reported to enhance the sensitivity of tumor cells to TRAIL agonists and promote apoptosis.

Cancer cells exhibit aberrant apoptotic signaling, including upregulation of anti-apoptotic molecules and suppression of proapoptotic molecules–. The high expression level of survivin, a member of the IAP family, the disrupted balance among the Bcl-2 family members, or the impaired activity of caspases, enhances cancer cell survival and is associated with tumor aggressiveness and the survival of cancer patients. Therefore, targeting apoptosis-related proteins has been one of the most active research fields in cancer therapeutics for the long-term and has achieved significant progress recently. The BH3 analog ABT-737 and its derivative ABT-263 act as pan-Bcl-2 inhibitors and simultaneously inhibit several members of Bcl-2 family proteins, including Bcl-2, Bcl-xL, and Bcl-W, to induce cell apoptosis,. BH3 analogs have shown therapeutic benefits for solid tumors and hematological malignancies,. The negative regulatory role of cFLIP in apoptosis makes it an attractive target molecule to treat cancer. The modulation of cFLIP expression and activity has been linked to the antitumor action of several targeted therapies, including those utilizing mTOR inhibitors and histone deacetylase inhibitors–.

Cell death-related pathways participate in the cellular stress response. Cancer cells exposed to various stresses (for example, DNA damages, oxidative stress) during oncogenic transformation and adaption to these stresses are required for cancer cells to survive. Oxidative stress results from the accumulation of ROS. ROS collectively include superoxide onion, hydrogen peroxide, and hydroxyl radical and regulate programmed cell death. Activation of death receptor-mediated signaling pathways has been associated with ROS production–. Wang et al. demonstrated ROS-mediated degradation of cFLIP, a negative regulator of Fas-induced apoptosis in lung epithelial cells. ROS can also trigger the intrinsic apoptotic cascade by disruption of the mitochondrial membrane potential, promoting cytochrome c detachment from cardiolipin and release to the cytosol and inducing oxidative mitochondrial DNA damage. Furthermore, ROS can activate apoptotic signaling via ASK1/JNK signaling. Accumulation of ROS can also activate autophagy. ROS-mediated oxidative modulation of Atg4 inhibited Atg4-delipidating activity, leading to the accumulation of LC3-PE on autophagosomal membranes and facilitating autophagosome formation. The interplay between ROS and autophagy contributes to cancer progression. In the early stage of cancer initiation, autophagy is proposed to play a tumor suppressor role by reducing ROS accumulation via the degradation of ROS-producing mitochondria, thus limiting genomic instability. However, at the later stage of tumor progression, autophagy may be exploited by cancer cells to promote their survival and oncogenic mutations. ROS-mediated programmed cell death makes ROS-based therapies an attractive strategy in cancer treatment. Moreover, although cancer cells have developed redox adaptation mechanisms to survive in a high oxidative environment, extensive studies have suggested that they are more vulnerable to oxidative stress caused by ROS-generating agents than normal cells, providing the selectivity of ROS-based therapies. Exogenous ROS-generating agents used as a single agent or in combination with other standard therapies have shown promise in pre-clinical studies–.

Cell death in other diseases

In addition to neurodegenerative diseases and cancer, cell death is associated with other diseases. Autophagy is involved in intestinal homeostasis, muscular dystrophy, stroke, pancreatitis, heart disease, liver disease, and type II diabetes–. Increasing the activity of Beclin1 has been proposed as a therapeutic strategy for these autophagy-related diseases. Apoptosis is also associated with ischemic stroke, acute central nervous system injury, heart disease, infectious diseases, autoimmune diseases. Therefore, targeting apoptotic pathways such as the broad-spectrum caspase inhibitor Q-VD-OPh, has been reported to cure diseases induced by apoptosis–. Necroptosis has been linked to the pathogenesis of ischemia-reperfusion injury, multiple sclerosis, myocardial infarction, stroke,, inflammatory disease, acute kidney injury, and microbial infection,,–. Nec-1, an inhibitor of RIPK1, has shown the efficacy by preventing necroptosis,,,,–.

Prospects

Apoptosis, autophagy, and necrosis, three types of cell death, have been studied separately and are considered independent processes. Recent advances in cell death research have changed our perception, leading us to consider these processes as interconnected with overlapping signaling pathways and cross-talk in response to different stresses. The existence of diverse regulated cell death pathways implicates the complexity of cell death programs but also provides novel therapeutic targets. Further studies are required to investigate the linkage within different cell death programs and identify key molecular factors that determine cell death under specific pathological conditions and that can be pharmacologically manipulated.

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    Wang Y, Tjandra N. Structural insights of tBid, the caspase-8-activated Bid, and its BH3 domain. J. Biol. Chem. 2013;288:35840-35851.

    Not in our library10.1074/jbc.m113.503680

  27. 27.

    Fan TJ, Han LH, Cong RS, Liang J. Caspase family proteases and apoptosis. Acta Biochem. Biophys. Sin. 2005;37:719-727.

    Not in our library10.1111/j.1745-7270.2005.00108.x

  28. 28.

    McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol. 2013;5:a008656.

    Not in our library10.1101/cshperspect.a008656

  29. 29.
    Role of Apoptosis in disease · 2012
    No notice
  30. 30.

    Ricci JE, et al. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell. 2004;117:773-786.

    Not in our library10.1016/j.cell.2004.05.008

  31. 31.

    Özören N, El-Deiry WS. Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia. 2002;4:551-557.

    Not in our library10.1038/sj.neo.7900270

  32. 32.

    Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999;13:1899-1911.

    Not in our library10.1101/gad.13.15.1899

  33. 33.

    Yuan S, Akey CW. Apoptosome structure, assembly, and procaspase activation. Structure. 2013;21:501-515.

    Not in our library10.1016/j.str.2013.02.024

  34. 34.

    Soldani C, et al. Poly (ADP-ribose) polymerase cleavage during apoptosis: when and where? Exp. Cell Res. 2001;269:193-201.

    Not in our library10.1006/excr.2001.5293

  35. 35.

    Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis cytochrome c-independent activation of caspase-9 by caspase-12. J. Biol. Chem. 2002;277:34287-34294.

    Not in our library10.1074/jbc.m204973200

  36. 36.

    Yoneda T, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J. Biol. Chem. 2001;276:13935-13940.

    Not in our library10.1074/jbc.m010677200

  37. 37.

    Tan Y, et al. Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. J. Biol. Chem. 2006;281:16016-16024.

    Not in our library10.1074/jbc.m601299200

  38. 38.

    Cheong H, Nair U, Geng J, Klionsky DJ. The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol. Biol. Cell. 2008;19:668-681.

    Not in our library10.1091/mbc.e07-08-0826

  39. 39.

    Kawamata T, Kamada Y, Kabeya Y, Sekito T, Ohsumi Y. Organization of the pre-autophagosomal structure responsible for autophagosome formation. Mol. Biol. Cell. 2008;19:2039-2050.

    Not in our library10.1091/mbc.e07-10-1048

  40. 40.

    Hamasaki M, et al. Autophagosomes form at ER–mitochondria contact sites. Nature. 2013;495:389-393.

    Not in our library10.1038/nature11910

  41. 41.

    Jung CH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell. 2009;20:1992-2003.

    Not in our library10.1091/mbc.e08-12-1249

  42. 42.

    He C, Klionsky DJ. Atg9 trafficking in autophagy-related pathways. Autophagy. 2007;3:271-274.

    Not in our library10.4161/auto.3912

  43. 43.

    Molejon MI, Ropolo A, Vaccaro MI. VMP1 is a new player in the regulation of the autophagy-specific phosphatidylinositol 3-kinase complex activation. Autophagy. 2013;9:933-935.

    Not in our library10.4161/auto.24390

  44. 44.

    Ohsumi Y. Ubiquitin and proteasomes: Molecular dissection of autophagy: two ubiquitin-like systems. Nat. Rev. Mol. Cell Biol. 2001;2:211-216.

    Not in our library10.1038/35056522

  45. 45.

    Mizushima N, et al. A protein conjugation system essential for autophagy. Nature. 1998;395:395-398.

    Not in our library10.1038/26506

  46. 46.

    Mizushima N, Noda T, Ohsumi Y. Apg16p is required for the function of the Apg12p–Apg5p conjugate in the yeast autophagy pathway. EMBO J. 1999;18:3888-3896.

    Not in our library10.1093/emboj/18.14.3888

  47. 47.

    Shintani T, et al. Apg10p, a novel protein‐conjugating enzyme essential for autophagy in yeast. EMBO J. 1999;18:5234-5241.

    Not in our library10.1093/emboj/18.19.5234

  48. 48.

    Ichimura Y, et al. A ubiquitin-like system mediates protein lipidation. Nature. 2000;408:488-492.

    Not in our library10.1038/35044114

  49. 49.

    Kirisako T, et al. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J. Cell Biol. 2000;151:263-276.

    Not in our library10.1083/jcb.151.2.263

  50. 50.

    Hanada T, et al. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J. Biol. Chem. 2007;282:37298-37302.

    Not in our library10.1074/jbc.c700195200

  51. 51.

    Diao J, Li L, Lai Y, Zhong Q. In vitro reconstitution of autophagosome–lysosome fusion. Methods Enzymol. 2017;365-376.

    Not in our library10.1016/bs.mie.2016.09.065

  52. 52.

    Cheng X, et al. Pacer mediates the function of class III PI3K and HOPS complexes in autophagosome maturation by engaging Stx17. Mol. Cell. 2017;65:1029-1043.

    Not in our library10.1016/j.molcel.2017.02.010

  53. 53.

    Itakura E, Kishi-Itakura C, Mizushima N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell. 2012;151:1256-1269.

    Not in our library10.1016/j.cell.2012.11.001

  54. 54.

    Nair U, et al. SNARE proteins are required for macroautophagy. Cell. 2011;146:290-302.

    Not in our library10.1016/j.cell.2011.06.022

  55. 55.

    Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 2011;27:107-132.

    Not in our library10.1146/annurev-cellbio-092910-154005

  56. 56.

    Galluzzi L, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:107-120.

    Not in our library10.1038/cdd.2011.96

  57. 57.

    Xu JC, et al. Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci. Transl. Med. 2016;8:333ra348.

    Not in our library10.1126/scitranslmed.aad0623

  58. 58.

    Shimada K, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol. 2016;12:497-503.

    Not in our library10.1038/nchembio.2079

  59. 59.

    Abe Ji, Morrell C. Pyroptosis as a regulated form of necrosis: PI + /annexin V–/high caspase 1/low caspase 9 activity in cells = pyroptosis? Circ. Res. 2016;118:1457-1460.

    Not in our library10.1161/circresaha.116.308699

  60. 60.

    Dwivedi N, Radic M. Citrullination of autoantigens implicates NETosis in the induction of autoimmunity. Ann. Rheum. Dis. 2014;73:483-491.

    Not in our library10.1136/annrheumdis-2013-203844

  61. 61.
    The role of TNF-α in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk · 2007
    Not checked
  62. 62.

    Vercammen D, et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 1998;187:1477-1485.

    Not in our library10.1084/jem.187.9.1477

  63. 63.

    Degterev A, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 2008;4:313-321.

    Not in our library10.1038/nchembio.83

  64. 64.

    Degterev A, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 2005;1:112-119.

    Not in our library10.1038/nchembio711

  65. 65.

    Weinlich R, Dillon CP, Green DR. Ripped to death. Trends Cell Biol. 2011;21:630-637.

    Not in our library10.1016/j.tcb.2011.09.002

  66. 66.

    Oberst A, Green DR. It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival. Nat. Rev. Mol. Cell Biol. 2011;12:757-763.

    Not in our library10.1038/nrm3214

  67. 67.

    Challa S, Chan FKM. Going up in flames: necrotic cell injury and inflammatory diseases. Cell Mol. Life Sci. 2010;67:3241-3253.

    Not in our library10.1007/s00018-010-0413-8

  68. 68.

    Kim S, Li J. Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia. Cell Death Dis. 2013;4:e716.

    Not in our library10.1038/cddis.2013.238

  69. 69.

    Seya T, et al. TLR3/TICAM-1 signaling in tumor cell RIP3-dependent necroptosis. Oncoimmunology. 2012;1:917-923.

    Not in our library10.4161/onci.21244

  70. 70.

    Kaiser WJ, et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature. 2011;471:368-372.

    Not in our library10.1038/nature09857

  71. 71.

    Silke J, Brink R. Regulation of TNFRSF and innate immune signalling complexes by TRAFs and cIAPs. Cell Death Differ. 2010;17:35-45.

    Not in our library10.1038/cdd.2009.114

  72. 72.

    Dempsey PW, Doyle SE, He JQ, Cheng G. The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev. 2003;14:193-209.

    Not in our library10.1016/s1359-6101(03)00021-2

  73. 73.

    Reiley WW, et al. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J. Exp. Med. 2007;204:1475-1485.

    Not in our library10.1084/jem.20062694

  74. 74.

    Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181-190.

    Not in our library10.1016/s0092-8674(03)00521-x

  75. 75.

    Kelliher MA, et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity. 1998;8:297-303.

    Not in our library10.1016/s1074-7613(00)80535-x

  76. 76.

    Dondelinger Y, et al. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death Differ. 2013;20:1381-1392.

    Not in our library10.1038/cdd.2013.94

  77. 77.

    Yang S, et al. Pellino3 targets RIP1 and regulates the proapoptotic effects of TNF-α. Nat. Commun. 2013;4:2583.

    Not in our library10.1038/ncomms3583

  78. 78.

    Orozco S, et al. RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ. 2014;21:1511-1521.

    Not in our library10.1038/cdd.2014.76

  79. 79.

    Wu X, et al. Distinct roles of RIP1–RIP3 hetero-and RIP3–RIP3 homo-interaction in mediating necroptosis. Cell Death Differ. 2014;21:1709-1720.

    Not in our library10.1038/cdd.2014.77

  80. 80.

    Murphy JM, et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013;39:443-453.

    Not in our library10.1016/j.immuni.2013.06.018

  81. 81.

    Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012;148:228-243.

    Not in our library10.1016/j.cell.2011.11.030

  82. 82.

    Scheidereit C. IκBkinase complexes: gateways to NF-κB activation and transcription. Oncogene. 2006;25:6685-6705.

    Not in our library10.1038/sj.onc.1209934

  83. 83.
    cIAPs Block Ripoptosome Formation, a RIP1/Caspase-8 Containing Intracellular Cell Death Complex Differentially Regulated by cFLIP Isoforms · 2011
    No notice
  84. 84.

    Cho Y, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137:1112-1123.

    Not in our library10.1016/j.cell.2009.05.037

  85. 85.

    He S, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell. 2009;137:1100-1111.

    Not in our library10.1016/j.cell.2009.05.021

  86. 86.

    Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805-820.

    Not in our library10.1016/j.cell.2010.01.022

  87. 87.

    He S, Liang Y, Shao F, Wang X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway. Proc. Natl. Acad. Sci. USA. 2011;108:20054-20059.

    Not in our library10.1073/pnas.1116302108

  88. 88.

    Kaiser WJ, et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 2013;288:31268-31279.

    Not in our library10.1074/jbc.m113.462341

  89. 89.

    Polykratis A, et al. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J. Immunol. 2014;193:1539-1543.

    Not in our library10.4049/jimmunol.1400590

  90. 90.

    Welz PS, Pasparakis M. A way to DAI. Cell Host. Microbe. 2012;11:223-225.

    Not in our library10.1016/j.chom.2012.02.003

  91. 91.

    Upton JW, Kaiser WJ, Mocarski ES. DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host. Microbe. 2012;11:290-297.

    Not in our library10.1016/j.chom.2012.01.016

  92. 92.
    Cationic nanocarriers induce cell necrosis through impairment of Na+/K+-ATPase and cause subsequent inflammatory response · 2015
    No notice
  93. 93.

    Zhang L, Wang H, Ding K, Xu J. FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells. Toxicol. Lett. 2015;236:43-59.

    Not in our library10.1016/j.toxlet.2015.04.015

  94. 94.

    Leist M, Jäättelä M. Four deaths and a funeral: from caspases to alternative mechanisms. Nat. Rev. Mol. Cell Biol. 2001;2:589-598.

    Not in our library10.1038/35085008

  95. 95.

    Wang X, et al. Necrotic cell death in response to oxidant stress involves the activation of the apoptogenic caspase-8/bid pathway. J. Biol. Chem. 2003;278:29184-29191.

    Not in our library10.1074/jbc.m301624200

  96. 96.

    Ashkenazi A., Dixit V. M. Death receptors: signaling and modulation. Science281, 1305–1308.

    Not in our library10.1126/science.281.5381.1305

  97. 97.

    Lin Y, Devin A, Rodriguez Y, Liu Zg. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 1999;13:2514-2526.

    Not in our library10.1101/gad.13.19.2514

  98. 98.

    Feng S, et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 2007;19:2056-2067.

    Not in our library10.1016/j.cellsig.2007.05.016

  99. 99.

    Moquin D, Chan FKM. The molecular regulation of programmed necrotic cell injury. Trends Biochem. Sci. 2010;35:434-441.

    Not in our library10.1016/j.tibs.2010.03.001

  100. 100.

    Holler N, et al. Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 2000;1:489-495.

    Not in our library10.1038/82732

  101. 101.

    Eguchi Y, Shimizu S, Tsujimoto Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res. 1997;57:1835-1840.

    Not in our library

  102. 102.

    Leist M, Single B, Castoldi AF, Kühnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med. 1997;185:1481-1486.

    Not in our library10.1084/jem.185.8.1481

  103. 103.

    Los M, et al. Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. Mol. Biol. Cell. 2002;13:978-988.

    Not in our library10.1091/mbc.01-05-0272

  104. 104.

    Szabó C, Dawson VL. Role of poly (ADP-ribose) synthetase in inflammation and ischaemia–reperfusion. Trends Pharmacol. Sci. 1998;19:287-298.

    Not in our library10.1016/s0165-6147(98)01193-6

  105. 105.

    Sims JL, Berger SJ, Berger NA. Poly (ADP-ribose) polymerase inhibitors preserve oxidized nicotinamide adenine dinucleotide and adenosine 5’-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis. Biochemistry. 1983;22:5188-5194.

    Not in our library10.1021/bi00291a019

  106. 106.

    Denecker G, et al. Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondria. Cell Death Differ. 2001;8:829-840.

    Not in our library10.1038/sj.cdd.4400883

  107. 107.

    Yu L, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304:1500-1502.

    Not in our library10.1126/science.1096645

  108. 108.

    Shimizu S, et al. Role of Bcl-2 family proteins in a nonapoptotic programmed cell death dependent on autophagy genes. Nat. Cell Biol. 2004;6:1221-1228.

    Not in our library10.1038/ncb1192

  109. 109.

    Bursch W. The autophagosomal–lysosomal compartment in programmed cell death. Cell Death Differ. 2001;8:569-581.

    Not in our library10.1038/sj.cdd.4400852

  110. 110.

    Li Y, et al. Suppression of autophagy enhanced growth inhibition and apoptosis of interferon-β in human glioma cells. Mol. Neurobiol. 2013;47:1000-1010.

    Not in our library10.1007/s12035-013-8403-0

  111. 111.

    Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 2007;8:741-752.

    Not in our library10.1038/nrm2239

  112. 112.

    Funderburk SF, Wang QJ, Yue Z. The Beclin 1–VPS34 complex–at the crossroads of autophagy and beyond. Trends Cell Biol. 2010;20:355-362.

    Not in our library10.1016/j.tcb.2010.03.002

  113. 113.

    Cao Y, Klionsky DJ. Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein. Cell Res. 2007;17:839-849.

    Not in our library10.1038/cr.2007.78

  114. 114.

    Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Curr. Opin. Cell Biol. 2004;16:663-669.

    Not in our library10.1016/j.ceb.2004.09.011

  115. 115.

    Erlich S, et al. Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy. 2007;3:561-568.

    Not in our library10.4161/auto.4713

  116. 116.

    Kihara A, Kabeya Y, Ohsumi Y, Yoshimori T. Beclin–phosphatidylinositol 3‐kinase complex functions at the trans‐Golgi network. EMBO Rep. 2001;2:330-335.

    Not in our library10.1093/embo-reports/kve061

  117. 117.

    Liang XH, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672-676.

    Not in our library10.1038/45257

  118. 118.

    He C, Levine B. The beclin 1 interactome. Curr. Opin. Cell Biol. 2010;22:140-149.

    Not in our library10.1016/j.ceb.2010.01.001

  119. 119.

    Morselli E, et al. Anti-and pro-tumor functions of autophagy. BBA-Mol. Cell Res. 2009;1793:1524-1532.

    Not in our library10.1016/j.bbamcr.2009.01.006

  120. 120.

    Robert G, et al. The anti-apoptotic Bcl-B protein inhibits BECN1-dependent autophagic cell death. Autophagy. 2012;8:637-649.

    Not in our library10.4161/auto.19084

  121. 121.

    Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell. 2008;19:5360-5372.

    Not in our library10.1091/mbc.e08-01-0080

  122. 122.

    Elgendy M, Sheridan C, Brumatti G, Martin SJ. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol. Cell. 2011;42:23-35.

    Not in our library10.1016/j.molcel.2011.02.009

  123. 123.

    Maiuri MC, et al. Functional and physical interaction between Bcl‐XL and a BH3‐like domain in Beclin‐1. EMBO J. 2007;26:2527-2539.

    Not in our library10.1038/sj.emboj.7601689

  124. 124.

    Wirawan E, et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 2011;1:e18.

    Not in our library10.1038/cddis.2009.16

  125. 125.

    Farkas T, Daugaard M, Jäättelä M. Identification of small molecule inhibitors of phosphatidylinositol 3-kinase and autophagy. J. Biol. Chem. 2011;286:38904-38912.

    Not in our library10.1074/jbc.m111.269134

  126. 126.

    Bell BD, et al. FADD and caspase-8 control the outcome of autophagic signaling in proliferating Tcells. Proc. Natl. Acad. Sci. USA. 2008;105:16677-16682.

    Not in our library10.1073/pnas.0808597105

  127. 127.

    Bonapace L, et al. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J. Clin. Invest. 2010;120:1310-1323.

    Not in our library10.1172/jci39987

  128. 128.

    Khan MJ, et al. Inhibition of autophagy rescues palmitic acid-induced necroptosis of endothelial cells. J. Biol. Chem. 2012;287:21110-21120.

    Not in our library10.1074/jbc.m111.319129

  129. 129.

    Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest. 2015;125:25-32.

    Not in our library10.1172/jci73939

  130. 130.

    Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 2011;13:132-141.

    Not in our library10.1038/ncb2152

  131. 131.

    Hosokawa N, et al. Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol. Biol. Cell. 2009;20:1981-1991.

    Not in our library10.1091/mbc.e08-12-1248

  132. 132.

    Gwinn DM, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell. 2008;30:214-226.

    Not in our library10.1016/j.molcel.2008.03.003

  133. 133.

    Bolster DR, Crozier SJ, Kimball SR, Jefferson LS. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J. Biol. Chem. 2002;277:23977-23980.

    Not in our library10.1074/jbc.c200171200

  134. 134.

    Egan DF, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331:456-461.

    Not in our library10.1126/science.1196371

  135. 135.

    Yang JC, et al. Selective targeting of breast cancer cells through ROS-mediated mechanisms potentiates the lethality of paclitaxel by a novel diterpene, gelomulide K. Free Radic. Biol. Med. 2011;51:641-657.

    Not in our library10.1016/j.freeradbiomed.2011.05.012

  136. 136.

    J-w Hwang, et al. Cigarette smoke-induced autophagy is regulated by SIRT1–PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch. Biochem. Biophys. 2010;500:203-209.

    Not in our library10.1016/j.abb.2010.05.013

  137. 137.

    Alexander A, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. Natl. Acad. Sci. USA. 2010;107:4153-4158.

    Not in our library10.1073/pnas.0913860107

  138. 138.

    Muñoz-Gámez JA, et al. PARP-1 is involved in autophagy induced by DNA damage. Autophagy. 2009;5:61-74.

    Not in our library10.4161/auto.5.1.7272

  139. 139.

    Huang Q, Shen HM. To die or to live: the dual role of poly (ADP-ribose) polymerase-1 in autophagy and necrosis under oxidative stress and DNA damage. Autophagy. 2009;5:273-276.

    Not in our library10.4161/auto.5.2.7640

  140. 140.

    Amaravadi RK, Thompson CB. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin. Cancer Res. 2007;13:7271-7279.

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    Micheau O. Cellular FLICE-inhibitory protein: an attractive therapeutic target? Expert. Opin. Ther. Targets. 2003;7:559-573.

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    Safa AR, Day TW, Wu CH. Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr. Cancer Drug. Targets. 2008;8:37-46.

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    Kubli DA, Gustafsson AringB. Mitochondria and mitophagy: the yin and yang of cell death control. Circ. Res. 2012;111:1208-1221.

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    Li FY, Jeffrey PD, Jong WY, Shi Y. Crystal structure of a viral flip insights into flip-mediated inhibition of death receptor signaling. J. Biol. Chem. 2006;281:2960-2968.

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    Xilouri M, Stefanis L. Autophagy in the central nervous system: implications for neurodegenerative disorders. CNS Neurol. Disord.-DR. 2010;9:701-719.

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    Walker LC, LeVine H. The cerebral proteopathies. Mol. Neurobiol. 2000;21:83-95.

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    Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 2009;118:5-36.

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    Lustbader JW, et al. ABAD directly links Aß to mitochondrial toxicity in Alzheimer’s Disease. Science. 2004;304:448-452.

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    Rohn TT. The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities. Apoptosis. 2010;15:1403-1409.

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    Rohn TT, et al. Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer’s disease brain. Neurobiol. Dis. 2011;43:68-78.

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    Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav. Brain. Res. 2009;196:168-179.

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  160. 160.

    Li Y, Yang X, Ma C, Qiao J, Zhang C. Necroptosis contributes to the NMDA-induced excitotoxicity in rat’s cultured cortical neurons. Neurosci. Lett. 2008;447:120-123.

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    Xu X, et al. Necrostatin‐1 protects against glutamate‐induced glutathione depletion and caspase‐independent cell death in HT‐22 cells. J. Neurochem. 2007;103:2004-2014.

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  162. 162.

    Zhu S, Zhang Y, Bai G, Li H. Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington’s disease. Cell Death Dis. 2011;2:e115.

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    Ravikumar B, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 2004;36:585-595.

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    Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 2002;11:1107-1117.

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    Wu YT, et al. Autophagy plays a protective role during zVAD-induced necrotic cell death. Autophagy. 2008;4:457-466.

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    Ravikumar B, Berger Z, Vacher C, O’kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum. Mol. Genet. 2006;15:1209-1216.

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

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    White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer. 2012;12:401-410.

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    Dikic I, Johansen T, Kirkin V. Selective autophagy in cancer development and therapy. Cancer Res. 2010;70:3431-3434.

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    Sotelo J, Briceno E, López-González MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 2006;144:337-343.

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  171. 171.

    Kondo Y, Kondo S. Autophagy and cancer therapy. Autophagy. 2006;2:85-90.

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    Wang K, et al. Quercetin induces protective autophagy in gastric cancer cells: involvement of Akt-mTOR-and hypoxia-induced factor 1α-mediated signaling. Autophagy. 2011;7:966-978.

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    Li J, et al. Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010;6:711-724.

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  174. 174.

    Ou WB, et al. HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status. Oncotarget. 2015;6:10510-10520.

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  175. 175.

    He G, et al. Overexpression of tumor suppressor TSLC1 by a survivin-regulated oncolytic adenovirus significantly inhibits hepatocellular carcinoma growth. J. Cancer Res. Clin. Oncol. 2012;138:657-670.

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  176. 176.

    Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer. 2002;2:277-288.

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  177. 177.

    Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat. Med. 1997;3:917-921.

    Not in our library10.1038/nm0897-917

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    Jäger U, et al. Follicular lymphomas9 BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t (14; 18) translocation. Blood. 2000;95:3520-3529.

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    Lawrence MS, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505:495-501.

    Not in our library10.1038/nature12912

  180. 180.

    Tse C, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68:3421-3428.

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    Oltersdorf T, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677-681.

    Not in our library10.1038/nature03579

  182. 182.

    Tan N, et al. Navitoclax enhances the efficacy of taxanes in non–small cell lung cancer models. Clin. Cancer Res. 2011;17:1394-1404.

    Not in our library10.1158/1078-0432.ccr-10-2353

  183. 183.

    Cragg MS, Harris C, Strasser A, Scott CL. Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat. Rev. Cancer. 2009;9:321-326.

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  184. 184.

    Kerr E, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 2012;19:1317-1327.

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  185. 185.

    Bangert A, et al. Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene. 2012;31:4677-4688.

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  186. 186.

    Pathil A, et al. HDAC inhibitor treatment of hepatoma cells induces both TRAIL‐independent apoptosis and restoration of sensitivity to TRAIL. Hepatology. 2006;43:425-434.

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    Vercammen D, et al. Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways. J. Exp. Med. 1998;188:919-930.

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    Gulbins E, et al. Fas‐induced programmed cell death is mediated by a Ras‐regulated O2– synthesis. Immunology. 1996;89:205-212.

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  189. 189.

    Sato T, et al. Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells. J. Immunol. 2004;173:285-296.

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  190. 190.

    Medan D, et al. Regulation of Fas (CD95)‐induced apoptotic and necrotic cell death by reactive oxygen species in macrophages. J. Cell Physiol. 2005;203:78-84.

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    Wang L, et al. The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation. J. Immunol. 2008;180:3072-3080.

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    Ryter SW, et al. Mechanisms of cell death in oxidative stress. Antioxid. Redox Signal. 2007;9:49-89.

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    Matsuzawa A, Ichijo H. Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochem. Biophys. Acta. 2008;1780:1325-1336.

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  194. 194.

    Dewaele M, Maes H, Agostinis P. ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy. 2010;6:838-854.

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  195. 195.

    Mathew R, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007;21:1367-1381.

    Not in our library10.1101/gad.1545107

  196. 196.

    Degenhardt K, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006;10:51-64.

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  197. 197.

    Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug. Discov. 2009;8:579-591.

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  198. 198.

    Pignanelli C, et al. Selective targeting of cancer cells by oxidative vulnerabilities with novel curcumin analogs. Sci. Rep. 2017;7:1105.

    Not in our library10.1038/s41598-017-01230-4

  199. 199.

    Ma D, et al. Cancer cell mitochondria targeting by pancratistatin analogs is dependent on functional complex II and III. Sci. Rep. 2017;7:42957.

    Not in our library10.1038/srep42957

  200. 200.

    Raj L, et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature. 2011;475:231-234.

    Not in our library10.1038/nature10167

  201. 201.

    Patel KK, Stappenbeck TS. Autophagy and intestinal homeostasis. Annu. Rev. Physiol. 2013;75:241-262.

    Not in our library10.1146/annurev-physiol-030212-183658

  202. 202.

    Levine B, Packer M, Codogno P. Development of autophagy inducers in clinical medicine. J. Clin. Invest. 2015;125:14-24.

    Not in our library10.1172/jci73938

  203. 203.

    Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147:728-741.

    Not in our library10.1016/j.cell.2011.10.026

  204. 204.

    Fleming A, Noda T, Yoshimori T, Rubinsztein DC. Chemical modulators of autophagy as biological probes and potential therapeutics. Nat. Chem. Biol. 2011;7:9-17.

    Not in our library10.1038/nchembio.500

  205. 205.

    Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27-42.

    Not in our library10.1016/j.cell.2007.12.018

  206. 206.

    Han W, Sun Y, Wang X, Zhu C, Blomgren K. Delayed, long-term administration of the caspase inhibitor Q-VD-OPh reduced brain injury induced by neonatal hypoxia-ischemia. Dev. Neurosci. 2014;36:64-72.

    Not in our library10.1159/000357939

  207. 207.

    Renolleau S, et al. Specific caspase inhibitor Q‐VD‐OPh prevents neonatal stroke in P7 rat: a role for gender. J. Neurochem. 2007;100:1062-1071.

    Not in our library10.1111/j.1471-4159.2006.04269.x

  208. 208.

    Carlson DL, Maass DL, White J, Sikes P, Horton JW. Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury. J. Appl. Physiol. 2007;103:323-330.

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  209. 209.

    Turmel H, et al. Caspase‐3 activation in 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP)‐treated mice. Mov. Disord. 2001;16:185-189.

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  210. 210.

    Linkermann A, et al. Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 2012;81:751-761.

    Not in our library10.1038/ki.2011.450

  211. 211.

    Ofengeim D, et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 2015;10:1836-1849.

    Not in our library10.1016/j.celrep.2015.02.051

  212. 212.

    Smith CC, et al. Necrostatin: a potentially novel cardioprotective agent? Cardiovasc, Drug Ther. 2007;21:227-233.

    Not in our library10.1007/s10557-007-6035-1

  213. 213.

    Wu J, et al. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res. 2013;23:994-1006.

    Not in our library10.1038/cr.2013.91

  214. 214.

    Kinsey GR, Okusa MD. Pathogenesis of acute kidney injury: foundation for clinical practice. Am. J. Kideny Dis. 2011;58:291-301.

    Not in our library10.1053/j.ajkd.2011.02.385

  215. 215.

    Wang X, et al. Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense. Proc. Natl. Acad. Sci. USA. 2014;111:15438-15443.

    Not in our library10.1073/pnas.1412767111

  216. 216.

    Kaiser WJ, Upton JW, Mocarski ES. Viral modulation of programmed necrosis. Curr. Opin. Virol. 2013;3:296-306.

    Not in our library10.1016/j.coviro.2013.05.019

  217. 217.

    Cho Y, McQuade T, Zhang H, Zhang J, Chan FKM. RIP1-dependent and independent effects of necrostatin-1 in necrosis and T cell activation. PLoS ONE. 2011;6:e23209.

    Not in our library10.1371/journal.pone.0023209

  218. 218.

    Oerlemans MI, et al. Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia–reperfusion in vivo. Basic. Res. Cardiol. 2012;107:270.

    Not in our library10.1007/s00395-012-0270-8

  219. 219.

    Peri P, Nuutila K, Vuorinen T, Saukko P, Hukkanen V. Cathepsins are involved in virus-induced cell death in ICP4 and Us3 deletion mutant herpes simplex virus type 1-infected monocytic cells. J. Gen. Virol. 2011;92:173-180.

    Not in our library10.1099/vir.0.025080-0

  220. 220.

    Xu X, et al. Synergistic protective effects of humanin and necrostatin-1 on hypoxia and ischemia/reperfusion injury. Brain Res. 2010;1355:189-194.

    Not in our library10.1016/j.brainres.2010.07.080

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