Recent advances in canonical versus non-canonical Ca2+-signaling-related anti-apoptotic Bcl-2 functions and prospects for cancer treatment

Cell fate is tightly controlled by a continuous balance between cell survival and cell death inducing mechanisms. B-cell lymphoma 2 (Bcl-2)-family members, composed of effectors and regulators, not only control apoptosis at the level of the mitochondria but also by impacting the intracellular Ca2+ homeostasis and dynamics. On the one hand, anti-apoptotic protein Bcl-2, prevents mitochondrial outer membrane permeabilization (MOMP) by scaffolding and neutralizing proapoptotic Bcl-2-family members via its hydrophobic cleft (region composed of BH-domain 1–3). On the other hand, Bcl-2 suppress pro-apoptotic Ca2+ signals by binding and inhibiting IP3 receptors via its BH4 domain, which is structurally exiled from the hydrophobic cleft by a flexible loop region (FLR). As such, Bcl-2 prevents excessive Ca2+ transfer from ER to mitochondria. Whereas regulation of both pathways requires different functional regions of Bcl-2, both seem to be connected in cancers that overexpress Bcl-2 in a life-promoting dependent manner. Here we discuss the anti-apoptotic canonical and non-canonical role, via calcium signaling, of Bcl-2 in health and cancer and evolving from this the proposed anti-cancer therapies with their shortcomings. We also argue how some cancers, with the major focus on diffuse large B-cell lymphoma (DLBCL) are difficult to treat, although theoretically prime marked for Bcl-2-targeting therapeutics. Further work is needed to understand the non-canonical functions of Bcl-2 also at organelles beyond the mitochondria, the interaction partners outside the Bcl-2 family as well as their ability to target or exploit these functions as therapeutic strategies in diseases.