A dual role for the anti apoptotic Bcl 2 protein in cancer: mitochondria versus endoplasmic reticulum.
Anti apoptotic Bcl 2 contributes to cancer formation and progression by promoting the survival of altered cells. Hence, it is a prime target for novel specific anti cancer therapeutics. In addition to its canonical anti apoptotic role, Bcl 2 has an inhibitory effect on cell cycle progression. Bcl 2 acts at two different intracellular compartments, the mitochondria and the endoplasmic reticulum (ER) At the mitochondria, Bcl 2 via its hydrophobic cleft scaffolds the Bcl 2 homology (BH) domain 3 (BH3) of pro apoptotic Bcl 2 family members. Small molecules (like BH3 mimetics) can disrupt this interaction, resulting in apoptotic cell death in cancer cells. At the ER, Bcl 2 modulates Ca(2+ signaling, thereby promoting proliferation while increasing resistance to apoptosis. Bcl 2 at the ER acts via its N terminal BH4 domain, which directly binds and inhibits the inositol 1,4,5 trisphosphate receptor (IP3R) the main intracellular Ca(2+ release channel. Tools targeting the BH4 domain of Bcl 2 reverse Bcl 2's inhibitory action on IP3Rs and trigger pro apoptotic Ca(2+ signaling in cancer B cells, including chronic lymphocytic leukemia (CLL) cells and diffuse large B cell lymphoma (DLBCL) cells. The sensitivity of DLBCL cells to BH4 domain targeting tools strongly correlated with the expression levels of the IP3R2 channel, the IP3R isoform with the highest affinity for IP3. Interestingly, bio informatic analysis of a database of primary CLL patient cells also revealed a transcriptional upregulation of IP3R2. Finally, this review proposes a model, in which cancer cell survival depends on Bcl 2 at the mitochondria and/or the ER. This dependence likely will have an impact on their responses to BH3 mimetic drugs and BH4 domain targeting tools. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.
Biochimica et biophysica acta