Le Pen J, Maillet L, Sarosiek K, Vuillier C, Gautier F, Montessuit S, Martinou J C, Letaï A, Braun F, Juin P P
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.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cell Death Dis. 2016 Feb 4;7(2):e2083. doi: 10.1038/cddis.2015.400.
Proapoptotic molecules directly targeting the BCL-2 family network are promising anticancer therapeutics, but an understanding of the cellular stress signals that render them effective is still elusive. We show here that the tumor suppressor p53, at least in part by transcription independent mechanisms, contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL. In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL, p53 also provides a death signal downstream of anti-apoptotic proteins inhibition. This death signal cooperates with BH3-induced activation of BAX and it is independent from PUMA, as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics. The acute sensitivity of mitochondrial priming to p53 revealed here is likely to be critical for the clinical use of BH3 mimetics.
直接靶向BCL-2家族网络的促凋亡分子是很有前景的抗癌治疗药物，但对于使其发挥作用的细胞应激信号仍不清楚。我们在此表明，肿瘤抑制因子p53至少部分通过非转录机制，促进细胞死亡诱导以及通过BCL-xL的BH3模拟抑制剂实现BAX的完全激活。除了适度促进化合物使BAX从BCL-xL释放的能力外，p53还在抗凋亡蛋白抑制的下游提供死亡信号。该死亡信号与BH3诱导的BAX激活协同作用，且不依赖于PUMA，因为增强的p53可以替代PUMA来促进BAX响应BH3模拟物的激活。此处揭示的线粒体启动对p53的急性敏感性可能对BH3模拟物的临床应用至关重要。
