BCL-2 protein family: attractive targets for cancer therapy

Abstract

Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy.

Keywords: Apoptosis; BCL-2 protein family; BH3-mimetic drugs; BH3-only proteins; Pro-apoptotic BCL-2 family members; Pro-survival BCL-2 proteins.

Fig. 1

The intrinsic pathway of apoptotic cell death is controlled by the BCL-2 protein family. This pathway is activated in response to various stress stimuli, such as oncogene activation or DNA damage. This causes an increase in the levels of the BH3-only proteins (e.g., PUMA, NOXA, BIM, BID, BAD) through diverse transcriptional as well as post-transcriptional processes. For example, the genes for PUMA and NOXA are directly transcriptionally activated by the tumour suppressor TP53/TRP53 (indicated in the dashed red box). The BH3-only proteins bind to the pro-survival BCL-2 proteins (e.g., BCL-2, BCL-XL, MCL-1) with high affinity. This unleashes the pro-apoptotic effector proteins BAK and BAX from their restraint by the pro-survival BCL-2 family members. The effectors of apoptosis, BAX and BAK, are also reported to be activated directly by certain BH3-only proteins, such as PUMA, BIM, and t-BID (the caspase activated form of BID). The activation of BAX and BAK allows these proteins to oligomerise and form pores in the outer mitochondrial membrane. This results in outer mitochondrial membrane permeabilisation (MOMP) causing release of cytochrome c from the space between the inner and the outer mitochondrial membranes into the cytoplasm. Upon release into the cytosol, cytochrome c drives the formation of a heptameric complex of the apoptotic protease activating factor 1 (APAF-1), called the apoptosome, which triggers the caspase cascade that causes the ordered demolition of the cells undergoing apoptosis

Fig. 2

Potential strategies targeting the intrinsic apoptotic pathway either by directly targeting the pro-apoptotic or the pro-survival BCL-2 family members or by targeting metabolic pathways and signal transducers to induce apoptosis by causing an increase in pro-apoptotic BH3-only proteins and/or a decrease in the pro-survival BCL-2 family members