|Year : 2015 | Volume
| Issue : 3 | Page : 514-524
Caspase-mediated crosstalk between autophagy and apoptosis: Mutual adjustment or matter of dominance
Rani Ojha1, Mohammad Ishaq2, Shrawan Kumar Singh1
1 Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Division of Cell Biology and Immunology, Institute of Microbial Technology, Chandigarh, India
|Date of Web Publication||9-Oct-2015|
Shrawan Kumar Singh
Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
In the last decade, it has been well established that programmed cell death (PCD) is not confined to apoptosis (type-I PCD) but cells may use different mechanisms of active self-destruction. One such mechanism is autophagy also called as type-II PCD, which is characterized by different morphological and biochemical features. It is not surprising that the demise of a cell either by PCD-I or by PCD-II is a well-controlled and complex process. The functional role of autophagy is not confined to the cell death through PCD-II, but interestingly it can also lead to cell death through apoptosis by enhancing the caspase activation. Autophagy may also act as a cell survival process by acting as a stress response, delaying caspase activation, and removing damaged organelles. Therefore, the crosstalk between apoptosis and autophagy is quite complex and sometimes contradictory as well, but unquestionably it is decisive to the overall fate of the cell. The molecular regulators of both pathways are inter-connected, and both share some factors that are critical for their respective execution. B-cell lymphoma-2, which was well known as an anti-apoptotic protein is now also considered as an anti-autophagic. Beyond the simplistic view of caspases in apoptosis, recent studies have uncovered unexpected functions of caspases in the regulation of autophagy, indicative of the novel frontiers lying ahead in the science of autophagy.
Keywords: Apoptosis, autophagy, cancer, caspases, programmed cell death
|How to cite this article:|
Ojha R, Ishaq M, Singh SK. Caspase-mediated crosstalk between autophagy and apoptosis: Mutual adjustment or matter of dominance. J Can Res Ther 2015;11:514-24
|How to cite this URL:|
Ojha R, Ishaq M, Singh SK. Caspase-mediated crosstalk between autophagy and apoptosis: Mutual adjustment or matter of dominance. J Can Res Ther [serial online] 2015 [cited 2019 Dec 9];11:514-24. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/514/163695
| > Introduction|| |
Autophagy and apoptosis are the two highly organized cellular processes that play vital role in embryonic development and tissue homeostasis. Dysregulation of these two processes have been associated with a number of pathological conditions, such as neurodegenerative diseases, autoimmune diseases and cancer. Various studies have very well established that autophagy and apoptosis extensively communicate with each other and the final outcome decides the fate of the cell during physiological and pathological conditions. Under stress conditions, cells initiate autophagy as a pro-survival mechanism to combat apoptosis. However, as stress increases towards a point of no return or threshold, cells block autophagy and initiates apoptotic cell death. The decision when to switch off this prosurvival autophagic process may mainly depend on the level of stress and is regulated by various proteins involved in autophagy and apoptosis. Caspases, a family of cysteinyl aspartate proteases, not only play central role in the execution of apoptosis but have been also shown to play vital role in the regulation of autophagy. In this review article, we have focused on the underlying mechanisms of caspases in directing the conversation between autophagy and apoptosis. These new functional aspects of caspases may be important in regulating the autophagy-apoptosis crosstalk during various pathophysiological conditions or under stress. Therefore understanding the caspase mediated crosstalk between autophagy and apoptosis may help to develop the therapeutic strategies by targeting these two vital processes.
Programmed cell death
Under normal physiological conditions, most cells of the body have a limited lifespan and are destined to die. The term programmed cell death (PCD) was introduced to highlight the fact that cells in the body do not die randomly but follow a sequence of highly ordered and stringently controlled steps.  Based on the morphological characteristics PCD has been divided into two types: PCD type-I and PCD type-II. Type-I PCD is commonly known as apoptosis and has been extensively studied since 1972 after Kerr et al.  Apoptosis is the most common form of PCD, however, alternative forms of PCD also exist and they may also be of biological importance particularly when apoptosis is defective. Type-II PCD also called as autophagy is a highly complex process and is currently a topic of intense research. 
Type-I programmed cell death or apoptosis
Apoptosis plays a fundamental role in shaping an immune system, developmental processes, tissue homeostasis, sexual differentiation, and elimination of infectious agents.  Cells undergoing apoptosis show distinct morphological and biochemical changes such as plasma membrane blebbing, loss of adhesion, cell shrinkage, nuclear condensation, DNA fragmentation, protein cross binding, and cleavage of various proteins by specific proteolytic enzymes called caspases. Caspases are cysteine proteases synthesized as zymogens and after activation play a central role in the effective onset of apoptosis.
Type-II programmed cell death or autophagy
Autophagy is a general term for the degradation of cytoplasmic components within lysosomes. This process is quite distinct from endocytosis mediated lysosomal degradation of extracellular and plasma membrane proteins. There are three types of autophagy: Macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy (simply autophagy) occurs at basal level in virtually all cells to perform homeostatic functions such as protein and organelle turnover. Autophagosome biogenesis involves three main steps: Initiation, elongation, and maturation. Each step is regulated and mediated by a set of specific proteins called autophagy-related proteins (Atg). During the transition from initiation to elongation and elongation to maturation, various protein complexes are recruited on to the autophagosomes while some others are separated apart. Although, the source of the membrane for autophagosome initiation is still mysterious, but the proteins involved in the initiation and other steps are now well identified.  Autophagy is activated as an adaptive catabolic process in response to different forms of metabolic stress including nutrient deprivation, growth factor depletion, hypoxia, and treatment with anticancer agents. Type-II or autophagic PCD is quite distinct from apoptosis as it occurs without caspase activation, change in nuclear morphology, and DNA fragmentation. 
Evidences of autophagic cell death
Autophagy is a nonselective, bulk degradation process and may even sequester and degrade a whole organelle such as mitochondria, endoplasmic reticulum, and peroxisomes. Therefore, it may be expected that excessive or uncontrolled autophagy may lead to cell death. Cells undergoing type-II PCD have a high number of vesicles indicating the presence of excessive autophagy. Significant reduction in cell death induced by various stimuli has been observed on inhibition of autophagy either by chemical inhibitors such as wortmannin (Wm), 3-methyl adenine (3-MA), and chloroquine (CQ) or by silencing of various Atg genes [Supplementary Table 1 [Additional file 1]]. Cells that normally undergo caspase-mediated apoptotic cell death were observed to follow autophagic cell death when the caspases were functionally inhibited by pan-caspase inhibitor z-VAD-fmk.  However, the most remarkable question in type-II PCD is how can a bulk degradation system initiate and execute the process of cell death?
Evidences against autophagic cell death
Autophagy was discovered as a cell survival response toward starvation; therefore, it may be possible that autophagy is basically initiated as a pro-survival stress response [Supplementary Table 2 [Additional file 2]]. Depolarized mitochondria, which are mediators of intrinsic apoptosis, are degraded through autophagy indicating that autophagy acts as a protective mechanism against apoptosis. When Bax/Bak deficient mouse embryonic fibroblasts (MEFs) are cultured in amino acids deprived medium, autophagy is activated to prolong survival, but cells eventually die of nutrient deficiency.  Autophagy has been shown to play important roles in rescuing the cells from caspase independent cell death (CICD). This study has raised an interesting question about autophagic cell death; as autophagy itself is considered a form of CICD. 
| > Crosstalk between apoptosis and autophagy|| |
At present no consensus can be made about factors, which determine whether autophagy is a cell survival or cell death process. However, from the studies of past few years it has become increasingly apparent that autophagy and apoptosis are intricately linked with each other to ensure the tight regulation of cellular homeostasis. Crosstalk between apoptosis and autophagy as a whole at "process level" is very complex and can be viewed in two separate aspects.
Crosstalk at process level
Autophagy antagonizes the effect of apoptosis and the extent may vary with the stimulus, cell type, and stress level. Inhibition of autophagy has been reported to enhance sensitivity toward apoptosis. ,, Indeed, inhibition of autophagy has been shown to enhance both caspase-dependent and independent cell death.  In contrast to bulk degradation, autophagy has been shown to degrade selectively the active caspase-8 and inhibit the tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) induced apoptosis.  A recent study has demonstrated that Atg7 forms a complex with caspase-9 and keeps a check on its apoptotic activity.  At the same time, for effective onset of cell death, autophagy is inhibited by degradation of Atg proteins by apoptotic proteins such as caspases and calpains. ,,
Autophagy may serve as a backup process. Autophagy enhances and positively contributes to the apoptosis has been shown by various studies. ,,, Autophagy may aid the compromised apoptotic machinery in some cancerous cells and clear the threshold of caspase activation necessary for the execution of apoptosis. B-cell lymphoma-2 (Bcl-2) overexpressing HeLa cells, which are resistant to intrinsic apoptotic pathway had increased caspase-8 activity when treated with the proteasomal inhibitor. The caspase-8 activation was found independent of mitochondrial outer membrane potential (MOMP) and caspase-3/7 activity but dependent on FAS-associated death domain (FADD)-mediated caspase-8 activation. Inhibition of autophagy by 3-MA or Atg5 knockdown abrogated caspase-8 activation. This study highlights the importance of autophagy in activation of initiator caspase-8 independent of MOMP and without the involvement of receptor related signal from outside the cells.  Puma- and Bax-induced autophagy have been demonstrated to contribute to the apoptosis in response to mitochondrial stress.  Another study concluded that poly ADP-ribose polymerase (PARP) and receptor interacting protein 1 are required for effective induction of autophagy, which enhances the apoptotic cell death.  Autophagy has also been demonstrated to play an important role in the formation of FADD, caspase-8, RIPK1 complex in T-cells, and MEFs. 
The mediators of autophagy and apoptosis interact and modulate the functional status of each other. These interactions usually occur through domains distinct from the ones involved in their classical functions [Table 1]. The same set of the proteins is involved in the autophagic cell death, pro-apoptotic autophagic process, as well as in a cell survival autophagic process. However, it remains to be elucidated, how the same protein can regulate these contrasting fates of the cell. There are various reports where an individual autophagy protein is involved in mediating the autophagic cell death. Under such conditions silencing of one autophagy protein inhibits both autophagy and cell death but silencing of another autophagy protein only inhibits autophagy but not cell death. Luo and Rubinsztein have shown that the interplay between Bcl-2 family proteins not only regulates apoptosis but autophagy as well. Bax, a pro-apoptotic protein was shown to decrease autophagy induction by mediating cleavage of Beclin-1.  Similarly, Bim inhibits Beclin-1-mediated autophagy independent of its pro-apoptotic functions.  Anti-autophagic functions of cellular FLICE-like inhibitory protein (c-FLIP), Bcl-2, and B-cell lymphoma extra-large are separate from their apoptotic functions. Furthermore, mitochondria localized Bcl-2 inhibits activating molecule in Beclin-1-regulated autophagy (AMBRA-1)-induced autophagy but ER localized Bcl-2 inhibits Beclin-1 induced autophagy.  Therefore, it is not surprising that the molecular crosstalk between these two pathways is very complex and sometimes contradictory as well. Crosstalk between autophagy and apoptosis at the molecular level can be dissected into three themes.
Crosstalk at molecular level
Autophagic proteins either directly or through their caspase cleaved fragments effectively induce apoptosis. Atg12 in its free form interacts with Bcl-2 and Mcl-1 and promotes staurosporine-induced apoptosis by acting upstream of mitochondria.  Apart from Atg12-Atg5 complex required in autophagosomes biogenesis, Atg12 has also been shown to form a complex with Atg3. Atg12-Atg3 complex is not involved in autophagosome biogenesis rather regulates mitochondrial integrity through mitophagy-mediated degradation of depolarized mitochondria.  Another Atg protein, Beclin-1 has been shown to augments cisplatin-induced apoptosis by enhancing caspase-9 activity  and has also been demonstrated to regulate the expression of caspase-9 in HeLa cells.  Autophagy adaptor protein p62 has also been found important in the effective activation of caspase-8 during extrinsic apoptotic pathway. 
Oncogenic Ras induces expression of pro-apoptotic protein, Noxa, which plays an important role in the autophagic cell death.  Lamy et al. have highlighted the role of caspase-10 in mediating the autophagic cell death.  Bcl-2 proteins have been demonstrated to regulate the nonapoptotic cell death in correlation with autophagy proteins.  Silencing of Bcl-2 induces autophagic cell death in MCF-7 cells.  Therefore, Bcl-2 family of proteins may be essentially called as regulators of PCD. Procaspase-3 expression but not activated caspase-3 has also been found important in the regulation of autophagic cell death in breast cancer cells. 
Atg5 has been shown to induce cell death without the involvement of autophagy. Interferon gamma (IFN-γ) has been reported to induce autophagic cell death with Atg5 playing a crucial role both in vacuole formation and cell death. Overexpression of Atg5 was shown to mimic the IFN-γ-induced cell death in these cell lines. Interestingly, silencing of Atg5 inhibited IFN-γ-induced cell death but had no effect on etoposide, staurosporine, and cisplatin-induced cell death. 
| > Caspases and autophagy|| |
Caspases act as molecular switches between autophagy and apoptosis by cleaving various Atg proteins  and the cleaved fragments, thus, generated have different functional activities and cellular localization [Figure 1] [and [Figure 2], [Table 2].
|Figure 1: Initiator caspases-mediated cleavage of autophagic proteins. Circumstances for initiator caspases mediated crosstalk between apoptosis and autophagy|
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|Figure 2: Effector caspases-mediated cleavage of autophagic proteins. The premise of effector caspases-mediated crosstalk between autophagy and apoptosis|
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Caspase-1 is functionally very complex and involved in apoptosis, necrosis, and pyroptosis.  Caspase-1 has been shown to play an important role in the regulation of autophagy. Autophagic proteins light chain 3B (LC3B), and Beclin-1 causes the activation of caspase-1, and the secretion of interleukin-1β (IL-1β) and IL-18.  During hypoxia, caspase-1 activation protects hepatocytes from cell death by increasing mitochondrial autophagy and subsequent clearance of damaged mitochondria. Caspase-1 increases the autophagic flux by upregulating Beclin-1 suggesting that caspase-1 mediated autophagy is a cell survival response.  Caspase-2 is the most conserved caspase, and its knockdown upregulates autophagic flux in rotenone treated primary neurons and delays rotenone-induced apoptosis. 
Caspase-3 is the effector caspase and upon activation cleaves various substrate proteins for the effective execution of apoptosis. Caspase-3 is also involved in the cleavage of various Atgs proteins and may, therefore, mediate functional crosstalk between autophagy and apoptosis. The first important study that highlighted the role of caspases in mediating crosstalk between autophagy and apoptosis through the cleavage of Atg proteins was by Cho et al., 2009. The authors demonstrated that upon treatment of TRAIL, Beclin-1 was cleaved, and this cleavage was reverted by z-VAD-fmk.  Ectopic expression of Beclin-1 suppresses cell death while reduction of Beclin-1 levels by siRNA sensitizes cells to TRAIL-induced cell death. Caspase-3 upon IL-3 deprivation leads to the cleavage of Beclin-1 and phosphoinositide 3-kinase, two critical component of autophagic machinery. The cleaved fragments generated do not possess any autophagic capability, but C-terminal fragment migrates to mitochondria and induces the release of pro-apoptotic factors which sensitizes these cells to apoptosis.  Zhu et al. have showed that Beclin-1 is a substrate of caspase-3 in staurosporine-induced apoptosis. Staurosporine treatment cleaves Beclin-1 into two fragments which abolishes its autophagic activity and enhances cell death. The interaction between Beclin-1 and Bcl-2 was completely disrupted by caspase-3-mediated cleavage. Interestingly, a noncleavable double mutant of Beclin-1 shows reduced capability to interact with Bcl-2, suggesting these amino acids are important for the proper interaction. This noncleavable double mutant inhibits autophagy and promotes cell death.  In Alzheimer's disease, Beclin-1 is cleaved by caspase-3, resulting in its compromised function. This finding suggests that cleavage of Beclin-1 may be a possible mechanism for the impairment of autophagy in neurodegenerative diseases.  Various apoptosis inducing agents were also demonstrated to cleave Beclin-1 through the activation of caspase-3 in Bax overexpressing HeLa cells. The noncleavable mutant (NCM) of Beclin-1 restored autophagy in the Bax overexpressing cells. The N-terminal fragment was predominantly located in the nucleus while C-terminal fragment was found in both cytoplasm and nucleus.  Beclin-1 seems to be the main target of caspase-3 [Figure 3] and cleavage site appears to depend on cell type and stimulus. The cleaved fragments have been found to localize in different regions and augment apoptotic response but lose their autophagic activity [Figure 4].
|Figure 3: Caspase-mediated cleavage of Beclin-1. The upper panel shows Beclin structure, and lower panel shows the different studies, which show the different caspase cleavage sites of Beclin-1|
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|Figure 4: The effect of caspase or calpain-mediated cleavage of Beclin-1 on cell viability. Apoptotic stimulus leads to induction of caspases or calpains which cleave Beclin-1 into N and C-terminal fragments. Cleaved fragments of Beclin-1 lost its autophagic activity. N-terminal fragments localized to nucleus, however, the function of nucleus localized N-terminal fragment is not explored. C-terminal fragment migrate to mitochondria which leads to release of cytochrome-c and ultimately cell death|
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Caspase-3 was also reported to cleave Atg4D at DEVD 63 K. A full-length Atg4D was shown to possess no delipidation activity against light chain associated protein (LC3) and gamma-aminobutyric acid receptor-associated protein (GABARAP), two Atg proteins; however a caspase-cleaved fragment of Atg4D effectively processed GABARAP but had no effect on LC3. Unexpectedly, the caspase cleavage of these Atg4 isoforms leads to increased autophagic flux, which acts as a cell survival response against starvation and staurosporine.  Sirois et al. have demonstrated the potential role of caspase-3 in the regulation of maturation and release of autophagic vesicles (AVs) in human endothelial cells. Under nutrient deprivation condition, LC3 conversion increase and AVs were released with concomitant activation of caspase-3 and cleavage of PARP. The z-VAD-fmk did not inhibit autophagy but negatively affect AVs maturation.  AMBRA-1 was also found to be an important target of apoptotic proteases for inhibiting autophagy and sensitizing cells to apoptosis. 
Caspase-8 is a predominant initiator caspase involved in the extrinsic apoptotic pathway and has been shown to be an important modulator of autophagy. Inhibition of caspase-8 expression by RNAi induces autophagy, which initiates the cell death program.  Therefore, autophagy may act as an alternative form of PCD, where apoptosis is compromised. DNA damaging agents have been reported to increase the autophagic flux in cytochrome-C (Cyt-C K1) mutant HCT116 colon cancer cell line, which is unable to assemble apoptosome. Beclin-1 knock down in Cyt-C K1 cells reduces cell survival after camptothecin (CPT) treatment suggesting that autophagy in these cells had a cell survival role. CPT treatment was demonstrated to cleave Beclin-1 at D133 and D146 in wild type HCT116 cells but not in HCT116 cells expressing Cyt-C K1. Beclin-1 cleavage was mediated strongly by caspase-8 and to a lesser degree by caspase-3. The NCM of Beciln-1 was shown to increase the induction of autophagy after CPT treatment.  Cleavage of Atg3 at amino acid 166 to 169 has also been shown by caspase-8, which leads to inhibition of autophagy. When Atg3 cleavage was inhibited either by z-VAD-fmk or by expressing NCM of Atg3, autophagy was restored back even after TNF-α treatment. Autophagy activation in mutant Atg3 or z-VAD-fmk treated cells was shown to act as a cell survival response.  You et al. have recently demonstrated the caspase-mediated cleavage of Atg5 and Beclin-1 in melanoma cell lines. The major cleavage product for Beclin-1 was 48 kDa and Atg5, it was approximately 30 kDa. Caspase-8 inhibitor fully inhibited the TRAIL-mediated cleavage of Beclin-1 and Atg5, while inhibitors of caspase-6, -3, -9 and -10 restored only partially. Interestingly, a caspase-8 inhibitor, which was more effective in reverting the TRAIL-mediated cleavage of Atg5 was also found more effective in inhibiting TRAIL-mediated cell death. , TRAIL treatment in various cancer cell lines results in activation of caspase-8, interestingly activated fragments of caspase-8 were not found in the cytosolic fraction except in Jurket cells. These cleaved fragments of caspase-8 were shown to be co-localized with autophagy markers, signifying autophagic degradation of active caspase-8. 
Caspase-9, -10, and -12
Beclin-1 overexpression in HeLa cells increases caspase-9 expression and subsequently induces cell death.  FR122047 (FR), a nonsteroidal anti-inflammatory drug induces autophagy and caspase-mediated cell death in MCF-7 cells. Surprisingly, inhibition of caspase-9 increased FR induced cell death by blocking autophagic flux at the maturation step.  Caspase-9 was shown to mediate increased autophagic flux by forming a complex with Atg7. Atg7-caspase-9 complex formation is enhanced by various autophagy inducing stimuli and decreased by apoptosis-inducing drugs. In spite of Atg7 masks the apoptotic function of caspase-9, the autophagic function of Atg7 was not altered by caspase-9.  The activation of caspase-10 was shown to be important for myeloma cell viability. Inhibition of caspase-10 induced autophagic cell death with no chromatin condensation and caspase-3 activation. Caspase-10 was shown to heterodimerize with c-FLIP, which mediates the partial activation of caspase-10. Bcl-2 associated transcription factor is an important cleavage target of caspase-10/c-FLIP L that accumulates following caspase-10 inhibition and contributes to autophagic cell death by disturbing the interaction between Beclin-1 and Bcl-2. This finding signifies the involvement of caspase-10 in an autophagic cell death.  Autophagy inducer rapamycin inhibits caspase-12-mediated polyQ72 aggregates-induced cell death. 
| > Concluding remarks|| |
Autophagy can determine the fate of the cell by various alternative ways. Under some experimental setups, autophagy is an important for the effective onset of apoptosis and is upregulated before caspase activation and thus precedes apoptosis. However, it is important to note that autophagy is not always compulsory for apoptosis, as an inhibition of autophagy only delays apoptosis but does not inhibit it. Another interesting scenario is that autophagy precedes apoptosis, but inhibition of autophagy increases cell death  and functional inactivation of caspases by z-VAD-fmk not only inhibits cell death but also restores autophagy [Table 3]. In this scenario, autophagy is upregulated as a cell survival response but once the stress reaches its threshold, caspases are activated which leads to the degradation of the autophagy machinery and subsequently induces cell death through apoptosis. However, the functional status of restored autophagy after z-VAD-fmk treatment remains unclear. The interplay between autophagy and apoptotic proteins is very complicated by the fact that autophagy can act both as a cell survival and cell death process. Elucidating the functional activities, regulatory mechanism, and dissecting the connections of autophagy as a cell survival and cell death mechanism with apoptosis will be a big challenge for both cancer biologists and basic scientists. Understanding the molecular mechanism, signaling cascades and the involvement of regulatory pathways involved in autophagy will be crucial in determining the context dependent physiological function of autophagy. This new knowledge will help for better patient stratification and will surely leads to the development of more efficient anticancer therapies.
|Table 3: The effect of caspase inhibition on autophagy and cell viability|
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Financial support and sponsorship
Ms. Rani Ojha and Mohammad Ishaq, recipient of Senior Research Fellowship (Indian Council of Medical and Research and Council of Scientific and Industrial Research respectively, New Delhi, India) deeply acknowledge the financial support for doctoral research work.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]