Abstract
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.
Highlights
P53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/B-cell lymphoma 2 (BCL-2) inhibitor ABT-263
A–C, Hep3B and PC3 cells were treated with various concentrations of metformin (Met) or ABT-263 (ABT) alone or their combination for 48 hours, and the cell viability was analyzed by Cell Counting Kit-8 (CCK-8) assay (A), and the Bliss Index was calculated (B)
We demonstrated that metformin and ABT-263 synergistically elicited apoptosis in p53-defective (but not (Continued.) The Bliss index was calculated as the ratio of observed effects to expected effects and Bliss Index > 1 represented synergistic effect.) B–D, HCT-116 p53þ/þ and HCT-116 p53À/À cells were treated with 10 mmol/L metformin (Met) or 5 mmol/L ABT-263 (ABT) alone or their combination for 48 hours (B) or 24 hours (C and D), and the cell viability was analyzed by CCK-8 assay (B) or Western blot analyses were performed with the antibody against cleaved-PARP (C) or other corresponding antibodies (D)
Summary
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. 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. 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. 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. It has been reported that p53 can restrain mTORC1, whereas p53 deficiency can enhance mTORC1 activity [8]. mTORC1, an
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