Modulation of Ca signaling by antiapoptotic Bcl-2 versus Bcl-xL: From molecular mechanisms to relevance for cancer cell survival.

Members of the Bcl-2-protein family are key controllers of apoptotic cell death. The family is divided into antiapoptotic (including Bcl-2 itself, Bcl-xL, Mcl-1, etc.) and proapoptotic members (Bax, Bak, Bim, Bim, Puma, Noxa, Bad, etc.). These proteins are well known for their canonical role in the mitochondria, where they control mitochondrial outer membrane permeabilization and subsequent apoptosis. However, several proteins are recognized as modulators of intracellular Ca signals that originate from the endoplasmic reticulum (ER), the major intracellular Ca-storage organelle. More than 25 years ago, Bcl-2, the founding member of the family, was reported to control apoptosis through Ca signaling. Further work elucidated that Bcl-2 directly targets and inhibits inositol 1,4,5-trisphosphate receptors (IPRs), thereby suppressing proapoptotic Ca signaling. In addition to Bcl-2, Bcl-xL was also shown to impact cell survival by sensitizing IPR function, thereby promoting prosurvival oscillatory Ca release. However, new work challenges this model and demonstrates that Bcl-2 and Bcl-xL can both function as inhibitors of IPRs. This suggests that, depending on the cell context, Bcl-xL could support very distinct Ca patterns. This not only raises several questions but also opens new possibilities for the treatment of Bcl-xL-dependent cancers. In this review, we will discuss the similarities and divergences between Bcl-2 and Bcl-xL regarding Ca homeostasis and IPR modulation from both a molecular and a functional point of view, with particular emphasis on cancer cell death resistance mechanisms.