Regulation of pro-apoptotic BH3-only proteins and its contribution to cancer progression and chemoresistance.

The BH3-only members of the Bcl-2 protein family function as damage sensors in the cell and initiate the apoptotic cascade. Apoptosis is the primary mechanism by which the body gets rid of genetically defective cells and is critical for preventing the accumulation of cells with tumorigenic potential. BH3-only proteins have evolved to respond to distinct forms of cellular stress or DNA damage by inactivating the protective function of the prosurvival members of the Bcl-2 family. Therefore, a downregulated expression or activity of these proteins may favour tumor development. Moreover, the pro-apoptotic proteins are required for the success of most cancer treatments, including chemotherapy. Resistance to chemotherapy, a common feature of cancer, often reflects an inability of tumor cells to undergo apoptosis. Deciphering the regulation and activity of the BH3-only proteins may provide the basis for novel therapeutic strategies aimed at promoting tumor cell death or enhancing susceptibility to chemotherapeutic agents. This review summarizes the current knowledge of BH3-only proteins and their contribution to tumorigenesis and chemoresistance.