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

Abstract

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.

The loss of endothelin-2 exhibits an anticancer effect in A549 human lung adenocarcinoma cell line

“…This complex promotes XIAP stability against ubiquitination/proteasomal destruction and synergistically inhibits caspase-9 activation (Dohi et al 2004). Accumulating evidence has shown that dual inhibition of survivin and XIAP effectively inhibits cancer proliferation and migration and induces apoptosis (Cao et al 2004;Yi et al 2015;Werner et al 2017;Li et al 2018;Chang et al 2020;Fang et al 2020). Therefore, the inhibition of ET-2 could be an effective strategy to inhibit LUAD progression through the dual inhibition of XIAP-survivin.…”

LncRNA H19 Impairs Chemo and Radiotherapy in Tumorigenesis

“…Induced-H19 ( Figure 3 B) enhances activation of NF-κb signaling promoting expression of pivotal oncogenic genes such as Blc-2 and XIAP—which are upregulated in several human gliomas and to protect from apoptosis cellular [ 100 , 101 ]. As is the case for BCL-2 or XIAP, H19 increases Cyclin D1 expression, which mediates cycle cellular transition leading to a higher proliferative ratio and preventing malignant cells from being retained in the G2/M phase [ 102 ]. As a consequence of enhancing expression of those oncogenic genes, TMZ fails to induce cell cycle arrest and apoptosis resulting in acquisition of resistance against this drug [ 103 ].…”

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

“…Therefore, the design of peptides that target the BIRC5/XIAP interface is important in the context of activating anti-tumor mechanisms in cells. Peptide Sur-X, with the sequence derived from the XIAP-binding region (K15-M38) of survivin and the cell-penetrating sequence from HIV Tat protein added to its N-terminal, was shown to destabilize the BIRC5/XIAP complex and induced growth inhibition and necroptosis in HCT116, HCT15, RKO, and HT29 cells and also had a pro-apoptotic effect in vivo in mouse xenograft models [ 121 ].…”