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Review
. 2015 Mar 17;112(6):957-62.
doi: 10.1038/bjc.2015.85.

Mitochondrial apoptosis: killing cancer using the enemy within

J Lopez  1 , S W G Tait  1
Affiliations
Review

Mitochondrial apoptosis: killing cancer using the enemy within

J Lopez et al. Br J Cancer. .

Abstract

Apoptotic cell death inhibits oncogenesis at multiple stages, ranging from transformation to metastasis. Consequently, in order for cancer to develop and progress, apoptosis must be inhibited. Cell death also plays major roles in cancer treatment, serving as the main effector function of many anti-cancer therapies. In this review, we discuss the role of apoptosis in the development and treatment of cancer. Specifically, we focus upon the mitochondrial pathway of apoptosis-the most commonly deregulated form of cell death in cancer. In this process, mitochondrial outer membrane permeabilisation or MOMP represents the defining event that irrevocably commits a cell to die. We provide an overview of how this pathway is regulated by BCL-2 family proteins and describe ways in which cancer cells can block it. Finally, we discuss exciting new approaches aimed at specifically inducing mitochondrial apoptosis in cancer cells, outlining their potential pitfalls, while highlighting their considerable therapeutic promise.

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Figures

Figure 1
Figure 1
Execution of mitochondrial apoptosis and escape mechanisms. Apoptotic stresses promote accumulation of BH3-only proteins leading to BAX/BAK oligomerisation, MOMP and release of intermembrane space proteins. Cytochrome c leads to apoptosome formation, which results in caspase activation and apoptosis. Smac and Omi neutralise the caspase inhibitor XIAP. Various strategies to escape apoptosis either by inhibiting MOMP or caspases are presented in red.
Figure 2
Figure 2
Mitochondrial priming model. In non-primed cells (top panel), mitochondria have a low BH3-only protein load leaving excess prosurvival BCL2 proteins to neutralise pro-apoptotic BH3-only proteins resulting from cytotoxic chemotherapy or BH3-mimetic treatment. In primed cancer cells (bottom panel), stresses such as oncogene activation lead to a high BH3-only protein load blocked by a compensatory increase in pro-survival BCL2 members. Additional pro-apoptotic stimuli result in excess activator BH3-only proteins that cause BAX/BAK activation, MOMP and death in these cells.
Figure 3
Figure 3
BH3-mimetic resistance mechanisms. In primed mitochondria, sensitiser BH3 mimetics promote MOMP by displacing activator BH3-only proteins. Resistance strategies discussed in the review are highlighted in red.
See this image and copyright information in PMC

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