Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
Department of Surgical Oncology, UMC Utrecht Cancer Centre, PO Box 85500, 3506 GA, Utrecht, The Netherlands.
Cell Death Dis. 2020 Apr 20;11(4):257. doi: 10.1038/s41419-020-2446-8.
A sophisticated network of BCL-2 family proteins regulates the mitochondria-associated (intrinsic) apoptosis pathway. Antiapoptotic members such as BCL-XL or MCL-1 safeguard the outer mitochondrial membrane and prevent accidental cell death in a functionally redundant and/or compensatory manner. However, BCL-XL/MCL-1-mediated "dual apoptosis protection" also impairs response of cancer cells to chemotherapy. Here, we show that hyperosmotic stress in the tumor environment abrogates dual BCL-XL/MCL-1 protection. Hypertonicity triggers upregulation of NOXA and loss of MCL-1 and thereby enforces exclusive BCL-XL addiction. Concomitant targeting of BCL-XL is sufficient to unlock the intrinsic apoptosis pathway in colorectal cancer cells. Functionally, "osmotic reprogramming" of the tumor environment grants contextual synthetic lethality to BCL-XL inhibitors in dually BCL-XL/MCL-1-protected cells. Generation of contextual synthetic lethality through modulation of the tumor environment could perspectively boost efficacy of anticancer drugs.
BCL-2 家族蛋白的复杂网络调控着与线粒体相关的（内在的）细胞凋亡途径。抗凋亡成员，如 BCL-XL 或 MCL-1，以功能冗余和/或补偿的方式保护外线粒体膜，防止意外的细胞死亡。然而，BCL-XL/MCL-1 介导的“双重凋亡保护”也会损害癌细胞对化疗的反应。在这里，我们表明肿瘤微环境中的高渗应激会破坏双重 BCL-XL/MCL-1 保护。高渗性会触发 NOXA 的上调和 MCL-1 的丢失，从而迫使细胞依赖 BCL-XL。同时靶向 BCL-XL 足以在结直肠癌细胞中解锁内在的细胞凋亡途径。从功能上讲，肿瘤微环境的“渗透重编程”赋予了双重 BCL-XL/MCL-1 保护的细胞对 BCL-XL 抑制剂的上下文合成致死性。通过调节肿瘤微环境产生上下文合成致死性可能会提高抗癌药物的疗效。
