Bcl-2 proteins and calcium signaling: complexity beneath the surface

Abstract

Antiapoptotic Bcl-2-family members are well known for their 'mitochondrial' functions as critical neutralizers of proapoptotic Bcl-2-family members, including the executioner multidomain proteins Bax and Bak and the BH3-only proteins. It has been clear for more than 20 years that Bcl-2 proteins can impact intracellular Ca(2+) homeostasis and dynamics. Moreover, altered Ca(2+) signaling is increasingly linked to oncogenic behavior. Specifically targeting the Ca(2+)-signaling machinery may thus prove to be a valuable strategy for cancer treatment. Over 10 years ago a major controversy was recognized concerning whether or not Bcl-2 proteins exerted their antiapoptotic functions via Ca(2+) signaling through lowering the filling state of the endoplasmic reticulum (ER) Ca(2+) stores or by suppressing Ca(2+) release from the ER without affecting the filling state of this Ca(2+) store. Further research from different laboratories indicated a wide variety of mechanisms by which Bcl-2-family members can impact Ca(2+) signaling. In this review, we propose that antiapoptotic Bcl-2-family members are multimodal regulators of intracellular Ca(2+)-signaling events in cell survival and cell death. We will discuss how different Bcl-2-family members impact cell survival and cell death by regulating Ca(2+) transport systems at the ER, mitochondria and plasma membrane and by impacting the organization of organelles and how these insights can be exploited for causing cell death in cancer cells. Finally, we propose that the existing controversy reflects the diversity of links between Bcl-2 proteins and Ca(2+) signaling, as certainly not all targets or mechanisms will be operative in every cell type and every condition.

Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

“…Indeed, the last decades, Bcl-2 proteins emerged as critical Edited by A. Villunger modulators of intracellular Ca 2+ dynamics [10,11]. As such, Bcl-2 also acts at the ER Ca 2+ stores where it inhibits inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP 3 Rs), a major class of intracellular Ca 2+ -release channels [12,13].…”

The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca 2+ signaling

“…Besides scaffolding pro-apoptotic Bcl-2-family members, anti-apoptotic Bcl-2 proteins also act through Ca 2+ -signaling modulation, a feature common among several oncomodulators [19,20]. Bcl-2 directly targets different Ca 2+ -flux systems, including intracellular Ca 2+ -release channels [21,22].…”

Inhibition of mitochondrial calcium uptake 1 in Drosophila neurons

“…The pro-survival role of Buffy in conditions of stress is well documented (M'Angale and Staveley, 2016a, b, c, d). However, this new role of Buffy, which might point to the conserved role of Bcl-2 proteins in the regulation of calcium signaling (Vervliet et al, 2016), deserves further investigation. Additionally, the rescue of defective phenotypes by Buffy highlights the pro-survival function of MICU1, being protective to the mitochondria as its loss can be compensated in yet unknown mechanisms by Buffy.…”