Bcl2 family proteins in carcinogenesis and the treatment of cancer

Abstract

Deregulation of Bcl2 family members is a frequent feature of human malignant diseases and causal for therapy resistance. A number of studies have recently shed light onto the role of pro- and anti-apoptotic Bcl2 family members in tumour-pathogenesis and in mediating the effects of classical as well as novel front-line anticancer agents, allowing the development of more efficient and more precisely targeted treatment regimens. Most excitingly, recent progress in our understanding of how Bcl2-like proteins maintain or perturb mitochondrial integrity has finally enabled the development of rational-design based anticancer therapies that directly target Bcl2 regulated events at the level of mitochondria. This review aims to give an overview on the most recent findings on the role of the Bcl2 family in tumour development in model systems of cancer, to relate these findings with observations made in human pathologies and drug-action.

Fig. 1

Cell death signalling regulated by the Bcl2 family. Prosurvival-members of the Bcl2 family preserve mitochondrial integrity by preventing activation of Bax and/or Bak until neutralised by BH3-only proteins. This leads to mitochondrial outer membrane permabilization, release of apoptogenic factors, including cytochrome c, required for apoptosome formation and activation of the caspase cascade. Activation of death receptors can licence the mitochondrial apoptosis pathway by caspase-8 mediated cleavage of Bid into tBid, connecting the extrinsic with the intrinsic apoptosis pathway in an amplification loop

Fig. 2

Tumour suppressing drugs acting via BH3-only proteins. Classical and novel anticancer agents trigger apoptosis by engaging one or more BH3-only proteins, by one or more different molecular mechanisms. Solid arrows indicate transcriptional activation; dashed arrows posttranslational stabilization; dotted arrows transcriptional and posttranslational activation/stabilization of BH3-only proteins in response to drug-treatment

Fig. 3

Summary of available BH3-mimetics and Bcl2 inhibitors. Chemical, non-peptidic and natural compounds currently tested for their ability to promote cell death by antagonizing the expression or pro-survival function of Bcl2-family members