Metformin Synergizes with BCL-XL/BCL-2 Inhibitor ABT-263 to Induce Apoptosis Specifically in p53-Defective Cancer Cells
Metformin Synergizes with BCL-XL/BCL-2 Inhibitor ABT-263 to Induce Apoptosis Specifically in p53-Defective Cancer Cells
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二甲双胍与 BCL-XL/BCL-2 抑制剂 ABT-263 协同作用，特异性诱导 p53 缺陷癌细胞凋亡
DOI：
10.1158/1535-7163.mct-16-0763
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发表时间：
2017-09-01
影响因子：
5.7
通讯作者：
He, Fengtian
中科院分区：
文献类型：
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作者：
Li, Xinzhe;Li, Bo;He, Fengtian
p53缺陷是多种恶性肿瘤中的常见事件，降低了包括BCL-XL/BCL-2抑制剂ABT-263在内的多种靶向化疗药物的敏感性。p53功能的丧失可以激活mTOR复合物1（mTORC 1），这可能使其成为易受攻击的靶标。二甲双胍已部分通过抑制mTORC 1显示出抑制效率。然而，目前尚不清楚mTORC 1激活是否赋予ABT-263抗性，以及二甲双胍是否可以在p53缺陷的情况下克服它。在这项研究中，我们首次证明二甲双胍和ABT-263通过协调各种p53缺陷癌细胞中的促凋亡机制协同诱导显著的凋亡。机制研究表明，二甲双胍通过减弱mTORC 1介导的MCL-1和生存素的帽依赖性翻译和减弱XIAP的内部核糖体进入位点（IRES）依赖性翻译来致敏ABT-263。同时，ABT-263通过破坏BCL-XL/BIM复合物来敏化二甲双胍。然而，二甲双胍和ABT-263对p53野生型（p53-WT）癌细胞没有协同杀伤作用，因为在野生型p53存在的情况下，二甲双胍和ABT-263显著诱导衰老相关分泌表型（SASP），并且SASP可以异常激活AKT/ERK-mTORC 1 - 4 EBP 1-MCL-1/survivin信号轴。使用相应的激酶抑制剂或针对不同SASP组分的中和抗体阻断轴使二甲双胍和ABT-263在p53-WT癌细胞中的共治疗效应敏化。体内实验表明，二甲双胍和ABT-263协同抑制肿瘤异种移植裸鼠中p53缺陷型（而非p53-WT）癌细胞的生长。这些结果表明，二甲双胍和ABT-263的组合可能是p53缺陷型癌症的一种新的靶向治疗策略。(C)2017年AACR。
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown antineoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the proapoptotic machineries in various p53-defective cancer cells. Mechanistic studies revealed that metformin sensitized ABT-263 via attenuating mTORC1-mediated cap-dependent translation of MCL-1 and survivin and weakening internal ribosome entry site (IRES) dependent translation of XIAP. Meanwhile, ABT-263 sensitized metformin through disrupting the BCL-XL/BIM complex. However, metformin and ABT-263 had no synergistic killing effect in p53 wild-type (p53-WT) cancer cells because the cotreatment dramatically induced the senescence-associated secretory phenotype (SASP) in the presence of wild type p53, and SASP could aberrantly activate the AKT/ERK-mTORC1-4EBP1-MCL-1/survivin signaling axis. Blocking the axis using corresponding kinase inhibitors or neutralizing antibodies against different SASP components sensitized the cotreatment effect of metformin and ABT-263 in p53-WT cancer cells. The in vivo experiments showed that metformin and ABT-263 synergistically inhibited the growth of p53-defective (but not p53-WT) cancer cells in tumor xenograft nude mice. These results suggest that the combination of metformin and ABT-263 may be a novel targeted therapeutic strategy for p53-defective cancers. (C) 2017 AACR.