Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis
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Shaoqing Shi1,2, Qiong Wang2,3, Jennings Xu2, Jun-Ho Jang2,4, Mabel T. Padilla2, Toru Nyunoya2,4, Chengguo Xing5, Lin Zhang1,3, Yong Lin2
1Department of Immunology, College of Basic and Forensic Medicine, Sichuan University, Chengdu, China
2Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA
3Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
4Division of Pulmonary and Critical Care Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USA
5Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA
Yong Lin, e-mail: [email protected]
Lin Zhang, e-mail: [email protected]
Keywords: autophagy, apoptosis, c-IAP, c-FLIP, cisplatin, Chal-24
Received: July 31, 2014 Accepted: November 08, 2014 Published: February 12, 2015
Drug resistance is a major hurdle in anticancer chemotherapy. Combined therapy using drugs with distinct mechanisms of function may increase anticancer efficacy. We have recently identified the novel chalcone derivative, chalcone-24 (Chal-24), as a potential therapeutic that kills cancer cells through activation of an autophagy-mediated necroptosis pathway. In this report, we investigated if Chal-24 can be combined with the frontline genotoxic anticancer drug, cisplatin for cancer therapy. The combination of Chal-24 and cisplatin synergistically induced apoptotic cytotoxicity in lung cancer cell lines, which was dependent on Chal-24-induced autophagy. While cisplatin slightly potentiated the JNK/Bcl2/Beclin1 pathway for autophagy activation, its combination with Chal-24 strongly triggered proteasomal degradation of the cellular inhibitor of apoptosis proteins (c-IAPs) and formation of the Ripoptosome complex that contains RIP1, FADD and caspase 8. Furthermore, the cisplatin and Chal-24 combination induced dramatic degradation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (cFLIPL) which suppresses Ripoptosome-mediated apoptosis activation. These results establish a novel mechanism for potentiation of anticancer activity with the combination of Chal-24 and cisplatin: to enhance apoptosis signaling through Ripoptosome formation and to release the apoptosis brake through c-FLIPL degradation. Altogether, our work suggests that the combination of Chal-24 and cisplatin could be employed to improve chemotherapy efficacy.
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