Sur-X, a novel peptide, kills colorectal cancer cells by targeting survivin-XIAP complex

Journal of Experimental & Clinical Cancer Research

Xiaonan Shi¹  Xiaojie Zhang¹  Yunpeng Liu¹  Wanxia Fang¹  Xiaofang Che¹  Kezuo Hou¹  Xiujuan Qu¹  Yizhe Wang²  Guohui Li³  Anhui Wang⁴ 

[1] Department of Medical Oncology, The First Hospital of China Medical University, 110001, Shenyang, China;Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, 110001, Shenyang, China;Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, 110001, Shenyang, China;Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, 110001, Shenyang, China;Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, 110001, Shenyang, China;Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116024, Dalian, China;Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116024, Dalian, China;State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, 116024, Dalian, China;

关键词: Colorectal cancer;    Survivin-XIAP complex;    Anticancer peptide;    Apoptosis;    Necroptosis;   

DOI  :  10.1186/s13046-020-01581-3

来源: Springer

【 摘 要 】

BackgroundSurvivin and XIAP are two important members of the inhibitor of apoptosis protein family and have been considered as potential targets for cancer treatment due to their overexpression in large variety of cancers including colorectal cancer. It has been reported that survivin and XIAP can synergistically inhibit apoptosis by forming survivin-XIAP complex. In this study, we aimed to design a peptide that targets the survivin-XIAP complex and elucidate its anticancer mechanisms in colorectal cancer cells.MethodsWe designed and synthetized Sur-X, the peptide targeting survivin-XIAP complex. The anticancer effects of Sur-X were evaluated both in vitro and in vivo. The underlying molecular mechanisms were also investigated.ResultsSur-X exhibited potent inhibitory effects on four colorectal cancer cell lines HCT116, HCT15, RKO and HT29, but not on human peritoneal mesothelial cell line HMrSV5. Mechanistically, Sur-X induced Caspase 9-dependent intrinsic apoptosis in colorectal cancer cells by disrupting the survivin-XIAP complex and subsequently destabilizing survivin and XIAP. Interestingly, we found that Sur-X can also promote necroptosis. It was demonstrated that Sur-X destroyed the interaction between XIAP and TAB1 in the XIAP-TAB1-TAK1 complex, leading to the instability of TAK1, an endogenous necroptosis inhibitor. Subsequently, the accelerated degradation of TAK1 attenuated its inhibition on necroptosis in colorectal cancer cells. Moreover, knockdown of TAK1 restored the sensitivity of TAB1-overexpressing colorectal cancer cells to Sur-X-induced necroptosis. The in vivo pro-apoptotic effect of Sur-X was confirmed by the enhanced TUNEL staining and the decreased expression of survivin and XIAP in tumor tissues from xenograft mouse models. In addition, extensive necrosis and weaker MLKL expression in xenografts provided evidence for the in vivo pro-necroptotic effect of Sur-X.ConclusionsPeptide Sur-X exhibits strong pro-apoptotic and pro-necroptotic effects in colorectal cancer cells and has a high clinical translation potential in the treatment of colorectal cancer.

【 授权许可】

CC BY