Key Points
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Cancer cells exhibit many phenotypes, such as genomic instability or oncogene activation, that ought to induce apoptosis, but they nonetheless survive. A block in apoptosis is a likely requirement for cancer maintenance.
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In cancer cells that overexpress BCL2 the protein itself is often largely bound to pro-apoptotic BH3-only proteins like BIM. In such circumstances we describe BCL2 and the cell as being 'primed'.
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BH3 profiling is a novel tool that exploits selective interaction between BH3 domains and anti-apoptotic BCL2 proteins to reveal the different ways cancer cells escape apoptosis. Certain cancer cells escape apoptosis by expression of BCL2; BH3 profiling can specifically identify these primed, BCL2-dependent cells.
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BCL2 expression does not necessarily confer a chemoresistant phenotype to cancer cells when selected for in previously untreated cells. If the expressed BCL2 is primed, sequestering large amounts of pro-apoptotic proteins such as BIM, it may actually relate to increased chemosensitivity.
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Primed cells are selectively sensitive to antagonists of anti-apoptotic BCL2 proteins like ABT-737. Primed cells might also be selectively more sensitive to conventional chemotherapy agents compared with cancer cells that use a different apoptotic block.
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It has long been suspected that cancer cells are more susceptible to cell death than normal cells. That some cancer cells appear to be primed for death in comparison with normal cells offers a possible biochemical explanation for this clinical observation.
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Small-molecule drugs that target BCL2 and related anti-apoptotic proteins are currently in early-phase clinical trials.
Abstract
Cancer cells survive despite violating rules of normal cellular behaviour that ordinarily provoke apoptosis. The blocks in apoptosis that keep cancer cells alive are therefore attractive candidates for targeted therapies. Recent studies have significantly increased our understanding of how interactions among proteins in the BCL2 family determine cell survival or death. It is now possible to systematically determine how individual cancers escape apoptosis. Such a determination can help predict not only whether cells are likely to be killed by antagonism of BCL2, but also whether they are likely to be sensitive to chemotherapy that kills by the intrinsic apoptotic pathway.
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Acknowledgements
I apologize to those many authors whose important work could not be included in this review owing to space constraints.
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Anthony G. Letai has received consulting fees from Abbott Laboratories. He is a co-founder of Eutropics Pharmaceuticals.
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FURTHER INFORMATION
Glossary
- Extrinsic apoptotic pathway
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The apoptotic pathway initiated by ligation of the tumour necrosis factor family of receptors. Following ligation, a death-inducing signalling complex is constructed, which induces activation of the initiator caspase 8, which in turn activates effector caspases such as caspase 3. This pathway can connect with the intrinsic pathway through caspase 8 cleavage and activation of the pro-death BCL2 family protein BID.
- Intrinsic or mitochondrial pathway
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The apoptotic pathway controlled by the BCL2 family that results in mitochondrial permeabilization by activated BAX and BAK. Multiple pro-apoptotic factors are released from the permeabilized mitochondria, including cytochrome c and SMAC, which induce caspase activation.
- Necrosis
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A type of cell death distinct from apoptosis, characterized by breakdown in the plasma membrane and release of intracellular contents. Though previously thought to be a passive process, it might also be regulated by a genetically encoded programme.
- Mitotic catastrophe
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A death resulting from failure of a cell to arrest before mitosis following DNA damage, resulting in severe aberrancies in chromosomal structure and segregation. It might share downstream events with apoptosis.
- Autophagy
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Literally, a cellular response in which the cell metabolizes its own contents and organelles to maintain energy production. Although such a process can eventually result in cell death, it can also be used to maintain cell survival under conditions of limiting nutrients.
- Initiator caspases
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That subset of the caspase family, including caspases 8 and 9, that are activated early in apoptotic signalling. Their cleavage targets are restricted, and include the effector caspases.
- Effector caspases
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That subset of the caspase family, including caspases 3 and 7, that are activated by initiator caspases in apoptotic signalling. Their cleavage targets are broadly distributed throughout the cell; activation of effector caspases is generally a terminal event for a cell.
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Letai, A. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer 8, 121–132 (2008). https://doi.org/10.1038/nrc2297
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DOI: https://doi.org/10.1038/nrc2297
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