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Sur-X, a novel peptide, kills colorectal cancer cells by targeting survivin-XIAP complex
Wanxia Fang1,2,3,4, Xiaofang Che1,2,3,4, Guohui Li5
1Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China.
Background:
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. 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.
Methods:
We 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.
Results:
Sur-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.
Conclusions:
Peptide 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.
Insights
A novel peptide, Sur-X, effectively targets the survivin-XIAP complex, inducing both apoptosis and necroptosis in colorectal cancer cells. This peptide shows significant potential for colorectal cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Survivin and XIAP are key inhibitors of apoptosis, often overexpressed in colorectal cancer.
- These proteins form a complex that synergistically inhibits apoptosis.
- Targeting this complex presents a promising strategy for colorectal cancer therapy.
Purpose of the Study:
- To design a peptide targeting the survivin-XIAP complex.
- To investigate the anticancer mechanisms of this peptide in colorectal cancer cells.
- To evaluate the therapeutic potential of the peptide in vitro and in vivo.
Main Methods:
- Design and synthesis of the peptide Sur-X.
- In vitro and in vivo evaluation of Sur-X's anticancer effects.
- Investigation of molecular mechanisms, including apoptosis and necroptosis pathways.
Main Results:
- Sur-X selectively inhibited colorectal cancer cell growth without affecting normal cells.
- Sur-X induced Caspase 9-dependent apoptosis by disrupting the survivin-XIAP complex.
- Sur-X promoted necroptosis by destabilizing TAK1, an inhibitor of necroptosis.
- In vivo studies confirmed Sur-X's pro-apoptotic and pro-necroptotic effects in tumor xenografts.
Conclusions:
- Peptide Sur-X demonstrates potent pro-apoptotic and pro-necroptotic activities in colorectal cancer.
- Sur-X exhibits significant potential for clinical translation in colorectal cancer treatment.
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