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 anti-neoplastic 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. Mol Cancer Ther; 16(9); 1806–18. ©2017 AACR .

中文翻译：

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二甲双胍与BCL-XL / BCL-2抑制剂ABT-263协同诱导特定于p53缺陷癌细胞的凋亡。

p53缺乏症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功能的丧失会激活mTOR复合体1（mTORC1），这可能使其成为易受攻击的目标。二甲双胍通过抑制mTORC1表现出部分抗肿瘤作用。但是，尚不清楚mTORC1激活是否赋予ABT-263抗性，二甲双胍能否在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缺陷癌细胞的促凋亡机制协同诱导了显着的细胞凋亡。机理研究表明，二甲双胍通过减弱mTORC1介导的MCL-1和survivin的帽依赖性翻译以及减弱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在p53野生型（p53-WT）癌细胞中没有协同杀伤作用，因为在存在野生型p53的情况下，共处理会显着诱导衰老相关的分泌表型（SASP），并且SASP可能异常激活AKT / ERK–mTORC1–4EBP1–MCL-1 / survivin信号转轴。使用相应的激酶抑制剂或针对不同SASP组分的中和抗体封闭轴，可增强二甲双胍和ABT-263在p53-WT癌细胞中的协同治疗作用。体内实验表明，二甲双胍和ABT-263协同抑制异种移植裸鼠中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缺陷癌的新型靶向治疗策略。分子癌疗法；16（9）; 1806–18。©2017 AACR。