Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance

In essentially all tissues that have self-renewal capacity, there exists a delicate balance between cell production by mitogenesis and cell loss due to programmed cell death (PCD), which maintains total cell numbers within physiologically appropriate ranges. Genetic alterations that either dysregulate the cell division process, resulting in faster cell proliferation, or that affect physiological cell death mechanisms that cause slower rates of cell loss, occur frequently in human tumor cells and contribute to the clonal expansion of cancer cells in vivo. PCD is an active form of cell suicide that sometimes requires new gene expression for its initiation and that in many, but not all, cases culminates in a characteristic set of biochemical and morphological events. These include genomic DNA cleavage by endonucleases, chromatin condensation (pyknosis), nuclear fragmentation, proteolysis of cytoskeletal and other proteins, plasma membrane blebbing, and cell shrinkage. In many ways, these biochemical events can be viewed as a form of cellular autodigestion in which the macromolecular components of cells are degraded so that their constituent subunits can be recycled in the body. When present in their classical form, the morphological events accompanying this type of cell death are broadly termed apoptosis. Though well known for its role in the normal physiological cell death mechanisms that maintain tissue homeostasis, a wide variety of pathological conditions and external factors can trigger the PCD pathway. Included among these apoptotic stimuli are essentially all chemotherapeutic drugs and radiation, a finding of considerable relevance to our understanding of how currently available treatments of cancer work and for devising strategies for improving them. In this review, the regulation of PCD by members of the bcl-2 family of proteins is discussed, primarily within the context of human cancers where abnormalities in the expression of BCL2 family genes frequently occur and contribute both to the origins of cancer and our difficulty in treating it.