Apoptotic cell death is widely considered a positive process that both prevents and treats cancer. Although undoubtedly having a beneficial role, paradoxically, apoptosis can also cause unwanted ...effects that may even promote cancer. In this Opinion article we highlight some of the ways by which apoptosis can exert oncogenic functions. We argue that fully understanding this dark side will be required to optimally engage apoptosis, thereby maximizing tumour cell kill while minimizing unwanted pro-tumorigenic effects.
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Apoptosis – Fueling the oncogenic fire Castillo Ferrer, Camila; Berthenet, Kevin; Ichim, Gabriel
The FEBS journal,
August 2021, Volume:
288, Issue:
15
Journal Article
Peer reviewed
Open access
Apoptosis, the most extensively studied form of programmed cell death, is essential for organismal homeostasis. Apoptotic cell death has widely been reported as a tumor suppressor mechanism. However, ...recent studies have shown that apoptosis exerts noncanonical functions and may paradoxically promote tumor growth and metastasis. The hijacking of apoptosis by cancer cells may arise at different levels, either via the interaction of apoptotic cells with their local or distant microenvironment, or through the abnormal pro‐oncogenic roles of the main apoptosis effectors, namely caspases and mitochondria, particularly upon failed apoptosis. In this review, we highlight some of the recently described mechanisms by which apoptosis and these effectors may promote cancer aggressiveness. We believe that a better understanding of the noncanonical roles of apoptosis may be crucial for developing more efficient cancer therapies.
Apoptosis exerts noncanonical pro‐oncogenic effects. Firstly, apoptotic cells release various paracrine factors that instruct cancer cells to proliferate, develop drug resistance, or avoid immune surveillance. Secondly, minority MOMP, which is characterized by permeabilization of few mitochondria and nonlethal caspase activation, triggers DNA damage and mutagenesis, and it increases cancer aggressiveness. Thirdly, mitochondria have pro‐oncogenic functions through either their cell‐to‐cell transfer or mitochondrial dynamics.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Regulated, programmed cell death is crucial for all multicellular organisms. Cell death is essential in many processes, including tissue sculpting during embryogenesis, development of the immune ...system and destruction of damaged cells. The best-studied form of programmed cell death is apoptosis, a process that requires activation of caspase proteases. Recently it has been appreciated that various non-apoptotic forms of cell death also exist, such as necroptosis and pyroptosis. These non-apoptotic cell death modalities can be either triggered independently of apoptosis or are engaged should apoptosis fail to execute. In this Commentary, we discuss several regulated non-apoptotic forms of cell death including necroptosis, autophagic cell death, pyroptosis and caspase-independent cell death. We outline what we know about their mechanism, potential roles in vivo and define outstanding questions. Finally, we review data arguing that the means by which a cell dies actually matters, focusing our discussion on inflammatory aspects of cell death.
Mechanical stress is known to fuel several hallmarks of cancer, ranging from genome instability to uncontrolled proliferation or invasion. Cancer cells are constantly challenged by mechanical ...stresses not only in the primary tumour but also during metastasis. However, this latter has seldom been studied with regards to mechanobiology, in particular resistance to anoikis, a cell death programme triggered by loss of cell adhesion. Here, we show in vitro that migrating breast cancer cells develop resistance to anoikis following their passage through microporous membranes mimicking confined migration (CM), a mechanical constriction that cancer cells encounter during metastasis. This CM-induced resistance was mediated by Inhibitory of Apoptosis Proteins, and sensitivity to anoikis could be restored after their inhibition using second mitochondria-derived activator of caspase (SMAC) mimetics. Anoikis-resistant mechanically stressed cancer cells displayed enhanced cell motility and evasion from natural killer cell-mediated immune surveillance, as well as a marked advantage to form lung metastatic lesions in mice. Our findings reveal that CM increases the metastatic potential of breast cancer cells.
Mammalian cytosine DNA methylation (5mC) is associated with the integrity of the genome and the transcriptional status of nuclear DNA. Due to technical limitations, it has been less clear if ...mitochondrial DNA (mtDNA) is methylated and whether 5mC has a regulatory role in this context. Here, we used bisulfite-independent single-molecule sequencing of native human and mouse DNA to study mitochondrial 5mC across different biological conditions. We first validated the ability of long-read nanopore sequencing to detect 5mC in CpG (5mCpG) and non-CpG (5mCpH) context in nuclear DNA at expected genomic locations (i.e. promoters, gene bodies, enhancers, and cell type-specific transcription factor binding sites). Next, using high coverage nanopore sequencing we found low levels of mtDNA CpG and CpH methylation (with several exceptions) and little variation across biological processes: differentiation, oxidative stress, and cancer. 5mCpG and 5mCpH were overall higher in tissues compared to cell lines, with small additional variation between cell lines of different origin. Despite general low levels, global and single-base differences were found in cancer tissues compared to their adjacent counterparts, in particular for 5mCpG. In conclusion, nanopore sequencing is a useful tool for the detection of modified DNA bases on mitochondria that avoid the biases introduced by bisulfite and PCR amplification. Enhanced nanopore basecalling models will provide further resolution on the small size effects detected here, as well as rule out the presence of other DNA modifications such as oxidized forms of 5mC.
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During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) ...has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term “minority MOMP.” Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis.
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•MOMP can occur in a minority of mitochondria•Minority MOMP triggers caspase activity but fails to kill cells•Minority MOMP-induced caspase activity causes DNA damage and genomic instability•Minority MOMP promotes cellular transformation and tumorigenesis
During apoptosis, mitochondrial outer membrane permeabilization (MOMP) is widespread, leading to rapid cell death. Here, Ichim et al. demonstrate that MOMP can also be engaged in a minority of mitochondria without killing the cell. Instead, minority MOMP triggers caspase-dependent DNA damage and genomic instability, thereby promoting transformation and tumorigenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Bcl‐2 proteins Bax and Bak can permeabilize the outer mitochondrial membrane and commit cells to apoptosis. Pro‐survival Bcl‐2 proteins control Bax by constant retrotranslocation into the cytosol ...of healthy cells. The stabilization of cytosolic Bax raises the question whether the functionally redundant but largely mitochondrial Bak shares this level of regulation. Here we report that Bak is retrotranslocated from the mitochondria by pro‐survival Bcl‐2 proteins. Bak is present in the cytosol of human cells and tissues, but low shuttling rates cause predominant mitochondrial Bak localization. Interchanging the membrane anchors of Bax and Bak reverses their subcellular localization compared to the wild‐type proteins. Strikingly, the reduction of Bax shuttling to the level of Bak retrotranslocation results in full Bax toxicity even in absence of apoptosis induction. Thus, fast Bax retrotranslocation is required to protect cells from commitment to programmed death.
Synopsis
Pro‐apoptotic proteins Bax and Bak kill cells by permeabilizing the outer mitochondrial membrane. Mitochondrial localization and thus apoptosis induction by both proteins is controlled by their retrotranslocation dynamics governed by the hydrophobicity of the C‐terminal membrane anchor.
The pro‐apoptotic Bcl‐2 protein Bak is retrotranslocated from the mitochondria into the cytosol dependent on pro‐survival Bcl‐2 proteins.
Bax and Bak retrotranslocate at different rates by the same retrotranslocation process.
Rapid Bax shuttling protects cells from apoptosis in the presence or absence of apoptotic stimuli.
The hydrophobicity of the membrane anchor determines shuttling and localization of Bax and Bak.
Pro‐apoptotic proteins Bax and Bak kill cells by permeabilizing the outer mitochondrial membrane. Mitochondrial localization and thus apoptosis induction by both proteins is controlled by their retrotranslocation dynamics governed by the hydrophobicity of the C‐terminal membrane anchor.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In cancer cells only, TLR3 acquires death receptor properties by efficiently triggering the extrinsic pathway of apoptosis with Caspase-8 as apical protease. Here, we demonstrate that in the absence ...of Caspase-8, activation of TLR3 can trigger a form of programmed cell death, which is distinct from classical apoptosis. When TLR3 was activated in the Caspase-8 negative neuroblastoma cell line SH-SY5Y, cell death was accompanied by lysosomal permeabilization. Despite caspases being activated, lysosomal permeabilization as well as cell death were not affected by blocking caspase-activity, positioning lysosomal membrane permeabilization (LMP) upstream of caspase activation. Taken together, our data suggest that LMP with its deadly consequences represents a "default" death mechanism in cancer cells, when Caspase-8 is absent and apoptosis cannot be induced.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and ...mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via tumor necrosis factor (TNF)-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Furthermore, although TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death.
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•Parkin-induced mitochondrial depletion can be used to define mitochondrial functions•Mitochondrial depletion prevents TNF-induced ROS, but not necroptosis•Activated RIPK3-induced necroptosis proceeds normally in mitochondria-depleted cells•ROS scavenger BHA delays TNF-induced necroptosis in mitochondria-depleted cells
Mitochondria have been implicated as key effectors in the execution of RIPK3-dependent necroptosis. Tait, Green, and colleagues directly test the importance of mitochondria in necroptosis by utilizing mitophagy to generate mitochondria-deficient cells. Mitochondrial depletion inhibits ROS production, but it does not affect necroptosis induced either by TNF or through direct activation of RIPK3. These results indicate that mitochondrial ROS accompanies rather than causes necroptosis and argue against a major role for mitochondria in executing necroptotic cell death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glioblastoma (GBM) is one of the cancers with the worst prognosis, despite huge efforts to understand its unusual heterogeneity and aggressiveness. This is mainly due to glioblastoma stem cells ...(GSCs), which are also responsible for the frequent tumor recurrence following surgery, chemotherapy or radiotherapy. In this study, we investigate the expression pattern of the anti-apoptotic BCL-xL protein in several GBM cell lines and the role it might play in GSC-enriched tumorspheres. We report that several GBM cell lines have an increased BCL-xL expression in tumorspheres compared to differentiated cells. Moreover, by artificially modulating BCL-xL expression, we unravel a correlation between BCL-xL and tumorsphere size. In addition, BCL-xL upregulation appears to sensitize GBM tumorspheres to newly developed BH3 mimetics, opening promising therapeutic perspectives for treating GBM patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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