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The Bcl-2 apoptotic switch in cancer development and therapy

Oncogene volume 26, pages 1324–1337 (2007)Cite this article

Abstract

Impaired apoptosis is both critical in cancer development and a major barrier to effective treatment. In response to diverse intracellular damage signals, including those evoked by cancer therapy, the cell's decision to undergo apoptosis is determined by interactions between three factions of the Bcl-2 protein family. The damage signals are transduced by the diverse ‘BH3-only’ proteins, distinguished by the BH3 domain used to engage their pro-survival relatives: Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and A1. This interaction ablates pro-survival function and allows activation of Bax and Bak, which commit the cell to apoptosis by permeabilizing the outer membrane of the mitochondrion. Certain BH3-only proteins (e.g. Bim, Puma) can engage all the pro-survival proteins, but others (e.g. Bad, Noxa) engage only subsets. Activation of Bax and Bak appears to require that the BH3-only proteins engage the multiple pro-survival proteins guarding Bax and Bak, rather than binding to the latter. The balance between the pro-survival proteins and their BH3 ligands regulates tissue homeostasis, and either overexpression of a pro-survival family member or loss of a proapoptotic relative can be oncogenic. Better understanding of the Bcl-2 family is clarifying its role in cancer development, revealing how conventional therapy works and stimulating the search for ‘BH3 mimetics’ as a novel class of anticancer drugs.

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Acknowledgements

The issues addressed here have benefited greatly from discussions with many colleagues, including in particular our senior colleagues Drs David Huang and Andreas Strasser, as well as Drs Simon Willis and Jamie Fletcher. This research is supported by the National Health and Medical Research Council (Program Grant 257502), the Leukmia and Lymphoma Society (SCOR Grant 7015-02) and the US National Cancer Institute (CA80188, CA43540).

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  1. Department of Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    J M Adams & S Cory

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Adams, J., Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26, 1324–1337 (2007). https://doi.org/10.1038/sj.onc.1210220

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