Proteins substrates of caspases (Blank and Shiloh 2007; Cohen et al 1997)
1.1. History, definition and classification
Life and death are essential parts of the natural cycle of all multicellular organisms. In metazoans, somatic cells divide normally during the process known as mitosis. Cell proliferation is tightly controlled, according to the organism needs. An increase in the number of cells takes place during growth and when one of these cells finishes its physiological function or detects DNA or cell damage, it undergoes a physiological process known as apoptosis that induces its own death. In humans about a hundred thousand cells are formed every second through mitosis, while a similar number is destroyed by apoptosis . This dynamic balance between proliferation and cell death is known as homeostasis. If altered, different pathologic processes such as carcinogenesis can take place. Besides its role in embryonic development, homeostasis maintenance and aging, apoptosis is also a defence mechanism by which infected, injured or mutated cells as a result of irradiation or chemotherapeutic drugs are eliminated. This type of cell death involves the activation of an evolutionary conserved and tightly regulated intracellular machinery that requires energy consumption . An important feature of apoptosis is that the cell is eliminated without triggering an immune response, avoiding thus tissue damage .
It is important to mention that a single stimulus can trigger more than one mechanism of cell death simultaneously within a cell. However, only the most efficacious mechanism will be prevalent.
2.1. Morphological and biochemical features
Morphological features that share both caspase-dependent and independent apoptotic pathways are: a) loss of plasma membrane symmetry and loss of cell-to-cell contact and cell round-up, b) chromatin condensation (picnosis) and fragmentation and nuclear breakdown, c) overall cell shrinkage and cytoskeleton alterations although the majority of the cell organelles remain intact, d) membrane blebbing and formation of the membrane-enclosed particles called apoptotic bodies that contain nuclear or cytoplasmic material and will be engulfed by phagocytes or neighbouring cells .
Because apoptotic cells are eaten so quickly, there are few dead cells left on tissue sections. This is the reason why apoptosis was neglected by pathologists for a long time, even though apoptosis is the main mechanism for discarding of harmful or unwanted cells in multicellular organisms.
Along with the morphological transformation described, there are several biochemical alterations that take place. For instance, activation of endonucleases, some of them dependent on Ca2+ and Mg2+ channels, that cleaves genomic DNA. In the apoptotic process, this event gives rise to internucleosomal DNA double-strand breaks with fragments of multiples of 180 bp, resulting in the typical pattern of
The most distinguishable feature of apoptosis is the formation of apoptotic bodies. On the other hand, oncosis is characterized by cytoplasmic swelling, dilation of organelles and vacuolization and plasma membrane blebbing. The cell will finally die by cytolysis, which is a typical hallmark of necrosis . Apoptotic cells can also lose their plasma membrane and eventually undergo a secondary necrosis. However, this phenomenon has only been observed
Apoptosis can be divided into three stages: initiation, integration/decision and execution/degradation . The initiation phase mainly depends upon cell type and apoptotic stimulus. The integration/decision phase consists of the activation of proteases, nucleases and other effector molecules. The execution/degradation phase involves morphological and biochemical changes that are common to all apoptotic mechanisms, regardless of the stimulus that initiated the process. The classical apoptosis is defined as a type of programmed cell death characterized by the activation of zymogens known as caspases, which are
3. Caspases: Executioners of the apoptotic process
Caspases are the effector molecules of apoptosis in mammals. They were first discovered mediating programmed cell death during development in the nematode
|DNA damage repair|
|Apoptosis and cell cycle|
|Rho GTPases regulator|
|Nuclear shape maintenance|
|Regulation of chromatin condensation|
|Sterol regulatory element binding proteins|
Caspase activity can be regulated both in a positive and in a negative manner. Negative caspase regulators are called Inhibitors of Apoptosis Proteins (IAPs) that bind to the catalytic site of caspases neutralizing its activity , or targeting them to degradation by ubiquinitation [20,21]. Some examples of IAPs are: XIAP, c-IAP1, c-IAP2, NAIP and survivin. On the other hand, Smac/DIABLO and Omi/HtrA2 act as positive regulators by inactivating IAPs .
4. Extrinsic and intrinsic apoptotic pathways
There are at least two main well characterized apoptotic routes: the death receptor or extrinsic pathway and the mitochondrial or intrinsic pathway. The extrinsic pathway plays a major role in tissue homeostasis and responds to external cues, coming especially from the immune system, whereas the intrinsic pathway is triggered as a response to various internal insults such as DNA damage, cytosolic calcium overload, starvation, oxidative stress, radiation, cytotoxic agents, etc., and involves mitochondrial destabilization [23,24].
The death receptor pathway is initiated by extracellular stimuli that are recognized by a subgroup of the tumour necrosis factor receptor (TNF-R) family named dead receptors (Fas/CD95/APO-1, TNFR1, TRAIL R1/DR4 and TRAIL R2/DR5). Upon binding of their ligands (FAS, TNFα and TRAIL) these receptors become activated and interact via their death domain with the protein motif
The intrinsic mitochondrial pathway is characterized by the action of B-cell lymphoma (Bcl-2) proteins. This family consists of proapoptotic and antiapoptotic proteins. The proapoptotic members promote mitochondrial outer membrane permeabilization (MOMP) and the antiapoptotic members counteract this action, so that the balance between these two groups of proteins determines the final outcome [27,28]. If the balance is in favour of the proapoptotic members, the outer mitochondrial membrane is permeabilized through pore formation and cytchrome c and other proteins such as Smac/DIABLO and Omi/HtrA2 are released to the cytosol. Then, cytochrome c binds to the adaptor protein Apaf-1 and dATP, forming the apoptosome, a catalytic complex that activates caspase-9 which in turn activates the executioner caspases.
The extrinsic and intrinsic pathways are interconnected through Bid. In some cases, when DISC formation is low, caspase-8 activation can induce MOMP through Bid cleavage, which translocates to the mitochondria and induces cytchrome c release, apoptosome formation and engagement of the caspase cascade .
5. Death receptors
Death receptors belong to the TNF-R superfamily of receptors. They participate in proliferation, differentiation, immune response, gene expression, survival and cell death. In fact, TNF-R1 and Fas (CD95/APO-1) are involved in apoptotic processes . Death receptors are stimulated by death ligands: TNF; Fas ligand (FasL) and
6. Role of mitochondria in cell death
MMP, a crucial event of the intrinsic mitochondrial apoptotic pathway, is considered a “point of no return” in the sequence of events leading to apoptosis. This phenomenon is associated with mitochondrial membrane potential loss (∆Ψm) that occurs as a result of assymetrical distribution of protons on both sides of the inner mitochondrial membrane. This irreversible process can take place before, during or after MOMP. The pore formation caused by Bcl-2 proteins induces MOMP, which leads to ∆Ψm dissipation, inhibition of ATP synthesis and ∆Ψm-dependent transport activities. Consequently, the respiratory change ceases, causing reactive oxygen species (ROS) generation and release of proteins confined within the inner mitochondrial space . The contribution of the inner mitochondrial permeabilization, however, is controversial. MOMP can also result from the phenomenon called mitochondrial permeability transition that implies the opening of a non-selective pore in the inner mitochondrial membrane known as the mitochondrial permeability transition pore complex .
6.1. Mechanisms of MOMP
The interplay between antiapoptotic and proapoptotic proteins decides the final fate of the damaged cell. Antiapoptotic proteins can be found in the outer mitochondrial membrane, in the cytoplasm or in the Endoplasmic Reticulum (ER). Some propapoptotic members such as Bax or Bid reside in the cytosol, but translocate to the outer membrane upon triggering of a death stimulus, where they oligomerize to form a channel, either with themselves or with membrane anchored-Bak or tBid. The importance of the interactions between proteins and lipids is becoming more evident. In fact, it is now thought that Bak or Bax destabilize lipid bilayers instead of forming pores. BH3-only proteins activity is transcriptionally and posttranslationally regulated. Bid, for instance, is regulated by caspase-8, cathepsins, granzyme B or calpain [37-39]. The proapototic protein Bad in inhibited through phosphorylation by Akt and activated through dephosphorylation by calcineurin .
The rise of mitochondrial matrix Ca2+ induces oxidative metabolism. However, upon apoptotic stimulus, Ca2+ can cause PTP opening, which can be transient and provide a fast calcium release mechanism, or persistent, giving rise to outer membrane rupture and release of apoptotic factors. Additionally, a different channel has been identified in the mitochondrion, composed of ceramide, a lipid that can form hydrogen bonds giving rise to ceramide structures that form channels which allow the efflux of proteins up to 60 kDa .
6.2. Cell death effectors released from mitochondria
The release of proteins from the intermembrane space and the loss of membrane-associated mitochondrial functions lead to cell death. Albeit is not clear the mechanism, mitochondrial destabilization provokes release of factors that mediate in caspase-dependent and independent pathways.
In addition, to the caspase-dependent effectors already mentioned, other caspase-independent proteins can be activated:
Besides its function as IAP inhibitor,
AIF and Endo G activity together with Omi/HtrA2 serine protease activity are considered responsible for the recently called
6.3. Afferent signals from other organelles
Mitochondria play a central role in programmed cell death pathways and integrate different signals coming from other organelles, being MMP, a point of no return, as already mentioned.
6.3.1. Nuclear DNA damage
The tumour suppressor p53 mediates DNA damage response, either by stimulating DNA damage response or by inducing apoptosis. As a transcription factor, p53 transactivates Bcl-2 proteins (Bad, Bid, Puma and Noxa) , which induce MMP and release of proteins from the intermembrane space . After DNA damage, p53 can also induce the expression of
6.3.2. Endoplasmic reticulum: Unfolded protein response
The ER has primordial roles in normal physiological and survival processes. These include intracellular calcium homeostasis, protein secretion and lipid biosynthesis .Apoptosis can be initiated as a consequence of stress in the ER. This stress condition can be caused by calcium homeostasis alteration, glucose deprivation, hypoxia, low redox potential, excessive protein synthesis or defective protein secretion. These insults can cause accumulation of unfolded proteins in the lumen of the ER, triggering an evolutionary conserved signalling pathway known as the Unfolded Protein Response (UPR) which can culminate in cell death. UPR consists of global protein synthesis reduction, synthesis induction of chaperones and other proteins related to protein folding and retro-translocation of misfolded or unfolded proteins from the ER to the cytosol, where they will be degraded by the proteasome . When the ER stress is sustained and ER function cannot be restored, UPR activates a specific apoptotic pathway. Caspase-12, which is localized in the ER, is activated by calcium-dependent proteases known as calpains .Once activated, caspase-12 activates caspase-9 without apoptosome intervention [61,62]. It has been postulated that ER stress can also activate caspase-8, which induces cytochrome c release through Bid processing [29,63]. In addition, ER stress can also initiate
Lysosomes are organelles that contain acidic hydrolases such as cathepsins. Rupture of lysosomes release cathepsins to the cytosol, where they can trigger apoptosis or necrosis. Cystatins, on the other hand, are cytosolic proteins that act as negative regulators of cathepsins when they are translocated from lysosomes to the cytosol. Apoptosis initiated in lysosomes follows a mitochondrion-dependent pathway associated to caspase activation. However, it has been shown that cathepsin D activates Bax and AIF release, triggering a caspase-independent apoptotic pathway . Furthermore, some cathepsins induce Bid cleavage , interaction with Bcl-2 proteins and permeabilization of the mitochondrial membrane .In addition, cathepsins can alter mitochondria functions by cleaving subunits of the oxidative phosphorylation complexes, inducing ROS generation .Lysosomes are essentially involved in
Several signals coming from the cytosol can induce MMP. These include: metabolites such as glucose 6-phospate and palmitate, ROS and activation of certain kinases: GSK3β, protein kinase C (PKC) δ,  and members of the JNK signalling pathway [38,66]. On the other hand, other molecules inactivate PTP and protect mitochondrial membrane from permeabilization, inhibiting apoptosis. These include: metabolites (ATP, glucose, NADH, UTP, etc.), antiapoptotic Bcl-2 family members, antioxidant enzymes such as glutathiones S transferase and prosurvival kinases such as Akt. In this sense, Akt can inhibit apoptosis by several mechanisms: activation of NFkB , inactivation of GSK3β and caspases and through hexokinase II-dependent mechanisms .
The cytoskeleton is composed of microtubules, microfilaments and intermediate filaments that play important roles in cell motility, polarity, attachment, shape maintenance, etc. Adherent cells can undergo a specific type of caspase-dependent cell death called
7. Parp proteolysis as an indicator of cell death
Poly-ADP-Ribose Polymerase (PARP) is a family of 16 nuclear enzymes, among which, the best characterized is PARP-1. PARPs have several functions in cell proliferation, cell death, DNA recombination and DNA repair. PARP-1 is a 116 kDa nuclear protein involved in DNA repair mechanisms. PARP synthesis is activated when DNA is fragmented in the presence of nuclear poly-ADP ribosylated proteins. In an early apoptotic stage, caspases cleave PARP resulting in an 89 kDa and a 24 kDa fragments . The smaller fragment irreversibly binds DNA fragment ends, impeding the access of DNA repair enzymes. Hence, PARP proteolysis facilitates nuclear disorganization and ensures irreversibility of the apoptotic process . PARP cleaves also takes place during necrosis. However, the fragments obtained are of different size . A role of PARP cleavage in autophagy induced by DNA damage has been recently suggested .
Macroautophagy (hereafter referred to as autophagy) is the most studied and prevalent form of autophagy in cells. This process begins with the formation of a “C” shaped double-membrane structure in the cytosol, called “omegasome”, which is formed from the ER (Initiation phase). Following this, the omegasome grows to form the “isolation membrane”, which elongates to engulf cytoplasmic components (Elongation phase). Then, the “isolation membrane” curves and closes to form a vacuole called the autophagosome (Maturation phase). As a result, portions of the cell cytoplasm and some organelles are sequestered in this vacuole. Finally, the outer membrane of the autophagosome fuses with the lysosomal membrane and the inner membrane (the autophagic body) carrying the cytosolic constituents enters the lysosome. The autophagic body is degraded in the lysosome by hydrolases and the resulting free amino acids and macromolecules are transported back into the cytosol for reuse . In this way, autophagy contributes to the maintenance of the cellular energy homeostasis, to the clearance of damaged organelles and to adaptation to environmental stresses . Accordingly, autophagy defects have been linked to a wide range of human pathologies, including cancer.
9. Mitotic catastrophe
The cell death process that takes place when mitosis cannot be completed is called mitotic catastrophe. This phenomenon is triggered as a consequence of perturbations of the mitotic machinery that governs appropriate chromosome segregation. The main hallmark of mitotic catastrophe is the enlarged cell size accompanied by multinucleation .Other features are chromatin condensation, DNA degradation, MMP, cyrochrome c release from the mitochondria and caspase activation .Some types of mitotic catastrophe, however, take place without intervention of caspases, what has been named caspase-independent mitotic death .Mitotic catastrophe results form the combination of deficient checkpoints (DNA and mitotic spindle) and DNA damage. Cells that evade the mitotic checkpoint and do not undergo apoptosis are prone to generate aneuploidy. Therefore, mitotic catastrophe is conceived as a device to avoid genomic instability. The players that take part in mitotic catastrophe are: cell cycle-dependent kinases (Cdk1, Aurora, Plk), cell cycle-check points proteins (Chk2, p53, p73), survivin, MCl-2, Blc-2 proteins, caspase-2, etc. . Mitotic catastrophe is a poorly defined molecular signalling pathway that precedes apoptosis, necrosis or senescence .
Necrosis is characterized by plasma membrane permeabilization, swelling and rupture. Necrosis can be accompanied in many instances by release of lysosomal hydrolases. Recently, a novel form of regulated necrosis has emerged and has been named
11. Apoptosis, chemoresistance and cancer
So far, we have reviewed generalities of different modalities of cell death that can take place after various pathologies: inflammation, stroke, ischemic injury, neurodegenerative disorders, viral infection, neoplasia, etc. The implication of apoptosis in cancer was initially observed as the type of cell death occurring in untreated tumours and in tumour regression after radiotherapy . The oncogenic process requires accumulation of diverse alterations within a cell that disrupt its normal homeostasis of cell death and growth. It is well established that excessive proliferation is not only due to oncogene activation but also to failure of the pathways controlling programmed cell death mechanisms . A malignant cell can be protected from cell demise though expression and/or activation of antiapoptotic factors (acting as oncogenes) or through inactivation of antiapoptotic factors (acting as tumour suppressor genes). Evasion of apoptosis is a hallmark of cancer . Dysregulation of apoptotic pathways renders cells resistant to antitumour strategies since the final outcome of radio and chemotherapy is frequently apoptosis of cancer cells. Therefore, resistance to cell death- in particular apoptotic cell death- is an important aspect of carcinogenesis, as it confers resistance to anticancer agents .In many tumours, chemoresistance acquisition is due to upregulation or modification of key elements of apoptosis control, such as Bcl-2, Bcl-XL and IAP family members . Other mechanisms are characterized by inactivating mutations in proapoptotic proteins, such as p53.
11.1. Defective checkpoints
11.2. Immunogenecity of cancer cell death
It is becoming more evident that the immune response facilitates the effects of chemotherapy. Physiological death avoids autoimmunity. However cancer cell death triggered by radiotherapy or some chemotherapeutic agents such as anthracyclines can be immunogenic .Immunogenic death involves changes in the composition of the cell membrane and the release of molecules called Damage Associated Molecular Patterns or alarmins. In particular, calreticulin has been shown to be crucial for immunogenic cancer cell death .The immune system determines the long-term success of antitumor therapies. It seems that mitochondrial events as well as the ER response in conjunction with autophagy can establish whether cancer cells die in response to chemotherapy . It has been found that calreticulin is the dominant pro-phagocytic signal on several cancers including neuroblastoma, non Hodgkin’s lymphoma and bladder cancer. However, calreticulin is counterbalanced by the “don´t eat me” signal CD47, which prevents cancer cell phagocytosis and is also highly expressed in these tumours . Moreover, since CD47 is expressed on the surface of all human cancer cells but not in normal cells, blocking CD47 function with antibodies is emerging as a novel potential cancer strategy .
12. Senescence and cancer
We have already mentioned that strong p53 activation induces apoptosis. However, Leontieva and colleagues have shown that a weak and sustained p53 activation during cell cycle arrest can promote a different type of cell demise known as
13. Autophagy and cancer
Regarding the role played by autophagy in cancer, mounting evidences suggest that autophagic cell death functions as a tumour suppressor mechanism. Several tumour suppressor proteins have been shown to induce autophagy. Supporting this idea, there are also several works showing that certain oncogenic proteins inhibit autophagy. Most of this oncogene products form part of the classic PI3K-Akt-mTOR pathway. In the following section, we summarize the literature on the role played by key tumour suppressors and oncogene products in the regulation of autophagy and the involvement of autophagic genes in cancer.
13.1. Tumour suppressor genes that regulate autophagy
To date, several tumour suppressor proteins that regulate autophagy have been described. These include: Beclin1, UV irradiation-resistance-associated gene (UVRAG), PTEN, Bcl-2, and p53. The majority of them act as autophagy inducers with the exception of p53 that is able to activate or inhibit autophagy.
13.2. Oncogenic genes that regulate autophagy
Most of the oncogenic genes that regulate autophagy described to date are key proteins of the PI3K-Akt-mTOR pathway. These proteins inhibit autophagy and promote carcinogenesis.
13.3. How does autophagy suppress tumourigenesis?
The combined data presented above strongly support the idea that autophagy functions as a tumour suppressor process. Consistent with this, oncogenes that have a role in autophagy are potent inhibitors of this process. Although the molecular mechanisms by which autophagy functions in tumour suppression are poorly defined, at least two mechanisms have been described:
Autophagy maintains the integrity of the genome
The first hypothesis is that autophagy may function as a housekeeping pathway to exert the quality control of organelles, proteins and DNA. Mathews and colleague observed that in autophagy deficient tumour cells, metabolic stress promotes the accumulation of p62, damaged mitochondria and ROS generation, promoting genomic instability and leading to oncogene activation and tumour progression [157,158]. Furthermore, immortalized mouse epithelial cells with a defect in ATG genes (loss of Beclin 1 or Atg 5) display increased DNA damage, centrosome abnormalities, numerical and structural chromosomal abnormalities and gene amplification, especially after ischemic stress.
However, the mechanisms through which autophagy preserves the integrity of the genome remains elusive. One possibility could be that autophagy may contribute to cell cycle regulation, for example by degrading organelles and/or proteins involved in the cell cycle checkpoints . Another possibility is that autophagy might simply function at a more general level to ensure the minimal amount of ATP and other metabolites required for DNA repair. Finally, autophagy may act by removing old and/or damaged organelles (for example, uncoupled mitochondria) which may act as a source of genotoxic chemical species such as ROS.
Autophagy limits necrosis-mediated inflammation
Necrosis normally results from physical injury in which the cell lyses and releases its intracellular contents, which activate the innate immune system and a wound-healing response . As a result, inflammatory cells are recruited and cytokines are released to promote cell growth to replace the damaged tissue [161,162].
In contrast, apoptosis may be the preferred means of cell demise for cells upon metabolic stress, as cells are eliminated without inflammation. However, in cancer cells with a defect in apoptosis, autophagy is induced for cell survival. Through autophagy, cells eliminate damaged organelles and may maintain their normal cellular function under adverse conditions of fluctuating oxygen and nutrient supply. However, this beneficial effect of autophagy functions during short term interruptions in nutrient availability, as in the long term (excess of autophagy) it can possibly lead to cell death.
A high proportion of tumours have been seen to present a defect both in autophagy and apoptosis. Degenhardt and colleagues have shown that the inhibition of both processes under conditions of metabolic stress generates a necrotic cell-death, suggesting that apoptosis and autophagy function to limit necrosis . In these necrotic tumours a persistent inflammatory infiltration and cytokine production exists, which is thought to promote tumour growth and thus, is associated with poor prognosis.
13.4. Role of autophagy in tumour survival
The data presented above strongly supports the idea that autophagy functions as a tumour suppressor process and that inhibition of autophagy leads to carcinogenesis. However, there are some circumstances where autophagy contributes to tumour survival promoting carcinogenesis:
Autophagy is induced by nutrient starvation
The survival role of autophagy during nutrient limitation is well established. When cells encounter environmental stresses such as nutrient starvation, autophagy can be activated and protects cells by preventing them from undergoing apoptosis. Through autophagy, starving cells degrade cytoplasmic material to generate both nutrients and energy . Consistent with this, during nutrient starvation, inhibition of autophagy promotes apoptosis .
Autophagy is induced by hypoxia
Hypoxia in tumours results from inadequate tumour vasculature and is associated with a more malignant phenotype, higher predisposition for metastasis, and poor prognosis. Hypoxic stress selects for cells that are resistant to apoptosis as well as poses a major barrier to chemotherapy and radiotherapy.
White and colleagues first showed that autophagy is induced specifically in the hypoxic core of tumours, where it promotes survival . Further studies have unveiled the molecular connections between hypoxia and the activation of autophagy. For example, it has been reported that when oxygen concentration falls below 5% hypoxia inducible factor 1 (HIF1) is activated and this transcription factor activates key autophagy inducers (BNIP3), which in turn activate the key autophagy complex formed by PI3K III [165,166]. Further mechanistic studies have revealed that induction of BNIP3 and BNIP3L in hypoxic cells disrupts the Becn1-Bcl-2 complex, thereby releasing Becn1 to induce autophagy .
The role of autophagy as a key mediator of survival of hypoxic cells is emerging so that the exact mechanisms underlying this phenotype remain unclear. Because chronic hypoxia leads to major metabolic perturbations in tumour tissues, one can postulate that by recycling basic cellular components, autophagy helps stressed cells cope with the increased metabolic demand . However, further studies are needed to validate this hypothesis.
Autophagy is induced in metastatic cells
Epithelial cells critically depend on cell adhesion to extracellular matrix (ECM) for proper growth and survival. Upon detachment of cells from the ECM, cells undergo anoikis, a type of apoptotic cell death that serves the homeostatic function of killing cells that have lost contact with the basement membrane . It has been shown that autophagy is induced in oncogene-transformed cells following matrix detachment . Similarly, in three dimensional (3D) epithelial cell culture models, autophagy is significantly increased in the detached luminal cells. Furthermore, when autophagy is inhibited accelerated luminal clearance occurs [158,169]. Altogether, these results suggest that autophagy is fundamental in anoikis resistance, a process exploited by tumour cells to survive after detachment from the primary site, as well as while migrating to distant metastatic sites .
Debnath and colleagues have shown that detachment induces autophagy in both nontumourigenic epithelial cell lines and in primary epithelial cells. Autophagy inhibition through siRNA for ATG genes inhibits detachment-induced autophagy and increases apoptosis. Remarkably, even when apoptosis is inhibited matrix-detached cells still exhibit autophagy. Moreover, inhibition of autophagy in MCF-10 acini enhances luminal apoptosis during morphogenesis and fails to elicit long-term luminal filling . Altogether, these results indicate that autophagy promotes epithelial cell survival during anoikis, including in detached cells harbouring antiapoptotic lesions.
14. Current therapeutic advances
In addition to inactivation of proliferative and prosurvival oncogenic pathways, current anticancer strategies deal with reactivation of cancer death cell signalling routes in order to induce tumour regression. The most promising cancer therapies that specifically target apoptosis, necrosis/necroptosis and autophagy are described in the following section.
14.1. Extrinsic apoptotic pathway
14.2. Intrinsic apoptotic pathway
Other IAP-targeted therapies such as XIAP and survivin antisense oligonucleotides have been developed . Antisense oligonucleotides against survivin synergize with etoposide in non small lung cancer cells . LY2181308 is a second generation antisense oligonucleotide being evaluated in clinical trials. In addition, a small molecule inhibitor of survivin, YM155, has shown potency in preclinical models and has entered phase II clinical trails .
14.3. DNA damage and cell cycle
Autophagy as a protective mechanism
A large series of anticancer drugs (both clinically approved and experimental) are able to induce a significant accumulation of autophagosomes in tumour cells both
Autophagy as a death mechanism
Although there is robust evidence indicating that autophagy has a protective role in cancer therapeutics, in certain cancer treatments, autophagy can kill cells by inducing
14.6. What determines if autophagy is cytoprotective or cytotoxic?
Autophagy is a process that allows cells to escape death or paradoxically leads to cell death. It is not yet understood what factors determine whether autophagy is cytoprotective or cytotoxic. It has been suggested that autophagy induced under pathological conditions functions as an adaptive cell response, allowing the cell to survive bioenergetic stress. However, autophagy is a process that destroys cellular content and organelles. In this way, it has been suggested that deregulated, excessive or persistent autophagy may lead to autophagic cell death. That is, the destruction of proteins and organelles may pass a threshold, leading to cell death. However, the point at which autophagy becomes autophagic cell death remains unclear. In this perspective, the dissection of the transition from autophagy to autophagic cell death and the cross-talking between apoptosis and autophagy may help to understand this process, leading to more efficacious treatments in cancer. In contrast, a different study has reported that when cells are subjected to prolonged growth factor deprivation or shortage of glucose and oxygen they can lose the majority of their mass via autophagy. However, when these cells are placed in optimal culture conditions, they are able to fully recover [163,213].This result suggests that cell death via autophagy may not be simply a matter of crossing a quantitative threshold of self-digestion.
14.7. Interplay among apoptosis, necrosis/necroptosis and autophagy
Cell death process
15. Concluding remarks
Programmed cell death mechanisms are intricate and usually interconnected processes. Evasion of cell death is a common feature of cancer cells leading to chemoresistance. Apoptosis, necrosis/necroptosis and autophagy are the main explored pathways that had gained interest among cancer biologists, as means to develop novel cancer therapeutics. Deeping our knowledge on the nexus between cell death and cancer will enable us to predict in a more refined manner the carcinogenic process and therefore, pave the way for a personalized approach to the disease.
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