Bcl-2 family proteins as regulators of oxidative stress

The Bcl-2 family of proteins includes pro- and anti-apoptotic factors acting at mitochondrial and microsomal membranes. An impressive body of published studies, using genetic and physical reconstitution experiments in model organisms and cell lines, supports a view of Bcl-2 proteins as the critical arbiters of apoptotic cell death decisions in most circumstances (excepting CD95 death receptor signaling in Type I cells). Evasion of apoptosis is one of the hallmarks of cancer [Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70], relevant to tumorigenesis as well as resistance to cytotoxic drugs, and deregulation of Bcl-2 proteins is observed in many cancers [Manion MK, Hockenbery DM. Targeting BCL-2-related proteins in cancer therapy. Cancer Biol Ther. 2003;2:S105-14; Olejniczak ET, Van Sant C, Anderson MG, Wang G, Tahir SK, Sauter G, et al. Integrative genomic analysis of small-cell lung carcinoma reveals correlates of sensitivity to bcl-2 antagonists and uncovers novel chromosomal gains. Mol Cancer Res. 2007;5:331-9]. The rekindled interest in aerobic glycolysis as a cancer trait raises interesting questions as to how metabolic changes in cancer cells are integrated with other essential alterations in cancer, e.g. promotion of angiogenesis and unbridled growth signals. Apoptosis induced by multiple different signals involves loss of mitochondrial homeostasis, in particular, outer mitochondrial membrane integrity, releasing cytochrome c and other proteins from the intermembrane space. This integrative process, controlled by Bcl-2 family proteins, is also influenced by the metabolic state of the cell. In this review, we consider the role of reactive oxygen species, a metabolic by-product, in the mitochondrial pathway of apoptosis, and the relationships between Bcl-2 functions and oxidative stress.