Trends in Cell Biology
Review
Special Issue: Translational Cell Biology
Evading apoptosis in cancer
Section snippets
Regulation of apoptosis in normal and cancer cells
Apoptosis is a cellular suicide program that organisms have evolved to eliminate unnecessary or unhealthy cells from the body in the course of development or following cellular stress. It involves a series of cellular events that ultimately leads to activation of a family of cysteine proteases called caspases. In response to various apoptotic stimuli, ‘initiator’ caspases (caspase-2, -8, -9, or -10) are activated. Initiator caspases, in turn, cleave and activate the zymogenic forms of
Transcriptional/translational regulation
Genomic and epigenomic abnormalities are a characteristic of cancer cells. This includes gene copy number amplification, gene deletion, gene silencing by DNA methylation, and activation (or inactivation) of transcription factors that have an impact on the expression of apoptotic regulators [13]. In addition, miRNAs negatively control gene expression by targeting the 3′ untranslated region (3′-UTR) of mRNAs, although they could function as tumor suppressors or oncogenes, depending on the target
Post-translational regulation
Various apoptotic regulators are modulated not only by transcriptional/translational machinery but also by post-translational modifications, including ubiquitination and phosphorylation. Protein ubiquitination is implicated in protein stability and is dynamically regulated through the ubiquitin/proteasome pathway [76], whereas phosphorylation can change protein functions 77, 78. It should be noted, however, that phosphorylation can also influence ubiquitination of the target protein by
Concluding remarks
To survive and proliferate, cancer cells need to override numerous barriers that otherwise would cause apoptosis. It is conceivable that cancer cells employ multiple mechanisms instead of a single pathway. Given the multiplicity of antiapoptotic mechanisms utilized by cancer cells, it is speculated that agents that can globally alter cancer's apoptotic resistance by targeting multiple pathways may provide us with the most valuable therapeutic benefits in the future of cancer treatment. To
Acknowledgments
The authors are grateful to Leta Nutt, Joseph Opferman, Marisa Buchakjian, and Matthew Ung for critical reading and feedback on the manuscript. This work was supported by an NCI Career Development Award R00 CA140948 (to M.K.) and a cancer center core grant P30 CA23108 (to the Norris Cotton Cancer Center).
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