Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma

摘要

Deregulated apoptosis is a key hallmark of cancer, and high expression of anti-apoptotic proteins is frequently observed in cancer cells. Apoptosis is initiated by ligation of death receptors on the cell surface or by the release of cytochrome c into the cytosol followed by formation of the apoptosome (intrinsic apoptosis). Among the most important regulators of apoptosis is the BCL-2 protein family, which consists of both pro- and anti-apoptotic proteins.1 The pro-apoptotic BCL-2 proteins BAX and BAK are essential for the execution of intrinsic apoptosis, as they mediate the release of cytochrome c from the mitochondrial intermembrane space. The anti-apoptotic proteins (BCL-2, BCL-XL, MCL-1, BCL-w, BCL2A1 and BCL-B) inhibit the activation of BAX and BAK, thus preventing the release of cytochrome c. BAX and BAK can be bound and inhibited directly by the anti-apoptotic BCL-2 proteins; alternatively, their activation can be inhibited by sequestration of BIM or related BCL-2 homology domain 3 (BH3)-only proteins. In this latter model, the release of BH3-only proteins from anti-apoptotic BCL-2 proteins is required in order to allow the BH3-only proteins to interact and directly activate BAX/BAK.