Abstract
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.
Highlights
Survivin 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
GAPDH was used as a loading control
Survivin and XIAP were overexpressed in colorectal cancer Online databases Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) were used to compare the expression of IAPs (NAIP, BIRC2, BIRC3, XIAP, BIRC5/survivin, BIRC6 and BIRC7, no data on BIRC8 was available) between colorectal cancer and normal tissues
Summary
Survivin 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. Survivin is the smallest member of inhibitor of apoptosis protein (IAP) family It is overexpressed in most cancers including colorectal cancer, but rarely expressed in normal differentiated tissues [4]. Through its interactions with multiple essential proteins such as Hsp, SMAC/DIABLO, XIAP, and the components of chromosomal passenger complex (CPC), survivin exerts two major functions: (i) inhibiting apoptosis and (ii) regulating cell division, both of which play key roles in the development of cancer [5,6,7]. Due to its specific overexpression in most cancer tissues, dual role in cell division regulation and apoptosis inhibition, and clinical significance, survivin has been established as an ideal target for anticancer therapy
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