Vervliet T, Parys J B, Bultynck G
KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Instituut (LKI), Leuven, Belgium.
Oncogene. 2016 Sep 29;35(39):5079-92. doi: 10.1038/onc.2016.31. Epub 2016 Mar 14.
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.
抗凋亡Bcl-2家族成员以其作为促凋亡Bcl-2家族成员（包括执行多结构域蛋白Bax和Bak以及仅含BH3结构域的蛋白）的关键中和剂的“线粒体”功能而闻名。20多年来，人们已经清楚地知道Bcl-2蛋白可以影响细胞内Ca(2+)的稳态和动态变化。此外，Ca(2+)信号的改变与致癌行为的联系越来越紧密。因此，特异性靶向Ca(2+)信号传导机制可能被证明是一种有价值的癌症治疗策略。10多年前，关于Bcl-2蛋白是否通过降低内质网（ER）Ca(2+)储存的充盈状态或通过抑制ER释放Ca(2+)而不影响该Ca(2+)储存的充盈状态来通过Ca(2+)信号传导发挥其抗凋亡功能，引发了一场重大争议。来自不同实验室的进一步研究表明，Bcl-2家族成员可以通过多种机制影响Ca(2+)信号传导。在这篇综述中，我们提出抗凋亡Bcl-2家族成员是细胞存活和细胞死亡过程中细胞内Ca(2+)信号事件的多模态调节因子。我们将讨论不同的Bcl-2家族成员如何通过调节内质网、线粒体和质膜上的Ca(2+)转运系统以及影响细胞器的组织来影响细胞存活和细胞死亡，以及如何利用这些见解来导致癌细胞死亡。最后，我们认为现有的争议反映了Bcl-2蛋白与Ca(2+)信号传导之间联系的多样性，因为肯定不是所有的靶点或机制在每种细胞类型和每种情况下都起作用。
