UMR 892 INSERM/6299 CNRS/Université de Nantes; Team 8 "Cell survival and tumor escape in breast cancer"; Institut de Recherche en Santé de l'Université de Nantes; Nantes, France.
Cell Cycle. 2013 Sep 15;12(18):2937-47. doi: 10.4161/cc.25972. Epub 2013 Aug 13.
It is widely accepted that anti-apoptotic Bcl-2 family members promote cancer cell survival by binding to their pro-apoptotic counterparts, thereby preventing mitochondrial outer membrane permeabilization (MOMP) and cytotoxic caspase activation. Yet, these proteins do not only function as guardians of mitochondrial permeability, preserving it, and maintaining cell survival in the face of acute or chronic stress, they also regulate non-apoptotic functions of caspases and biological processes beyond MOMP from diverse subcellular localizations and in complex with numerous binding partners outside of the Bcl-2 family. In particular, some of the non-canonical effects and functions of Bcl-2 homologs lead to an interplay with E2F-1, NFκB, and Myc transcriptional pathways, which themselves influence cancer cell growth and survival. We thus propose that, by feedback loops that we currently have only hints of, Bcl-2 proteins may act as rulers of survival signaling, predetermining the apoptotic threshold that they also directly scaffold. This underscores the robustness of the control exerted by Bcl-2 homologs over cancer cell survival, and implies that small molecules compounds currently used in the clinic to inhibit their mitochondrial activity may be not always be fully efficient to override this control.
人们普遍认为，抗凋亡 Bcl-2 家族成员通过与促凋亡的同类物结合来促进癌细胞存活，从而防止线粒体外膜通透性 (MOMP) 和细胞毒性半胱天冬酶的激活。然而，这些蛋白质不仅作为线粒体通透性的守护者，在面对急性或慢性应激时保持其通透性并维持细胞存活，它们还通过多种亚细胞定位和与 Bcl-2 家族以外的众多结合伙伴的复杂相互作用，调节半胱天冬酶的非凋亡功能和 MOMP 以外的生物学过程。特别是，一些 Bcl-2 同源物的非典型作用和功能导致与 E2F-1、NFκB 和 Myc 转录途径相互作用，这些途径本身影响癌细胞的生长和存活。因此，我们提出，通过我们目前仅有的一些反馈回路，Bcl-2 蛋白可能作为存活信号的调节者，预先确定它们也直接支撑的凋亡阈值。这突显了 Bcl-2 同源物对癌细胞存活的控制的稳健性，并暗示目前临床上用于抑制其线粒体活性的小分子化合物可能并不总是能够完全有效地克服这种控制。
