Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis.
机构：[1]Department of Immunology, College of Basic and Forensic Medicine, Sichuan University, Chengdu, China[2]Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA[3]Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China[4]Division of Pulmonary and Critical Care Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USA[5]Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA
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.
基金：
This study was partly supported by grants from NIEHS/NIH (R01ES017328), NCI/NIH (R01CA142649), and the Office of Science (BER), U.S. Department of Energy (DE-FG02-09ER64783) and National Natural Science Foundation of China (No. 81272821).
语种：
外文
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中科院(CAS)分区：
出版当年[2015]版：
大类|1 区医学
小类|2 区肿瘤学3 区细胞生物学
最新[2023]版：
无
第一作者：
第一作者机构：[1]Department of Immunology, College of Basic and Forensic Medicine, Sichuan University, Chengdu, China[2]Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA
通讯作者：
通讯机构：[1]Department of Immunology, College of Basic and Forensic Medicine, Sichuan University, Chengdu, China[3]Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
推荐引用方式(GB/T 7714)：
Shi Shaoqing,Wang Qiong,Xu Jennings,et al.Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis.[J].Oncotarget.2015,6(3):1640-51.doi:10.18632/oncotarget.2746.
APA：
Shi Shaoqing,Wang Qiong,Xu Jennings,Jang Jun-Ho,Padilla Mabel T...&Lin Yong.(2015).Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis..Oncotarget,6,(3)
MLA：
Shi Shaoqing,et al."Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis.".Oncotarget 6..3(2015):1640-51
医学