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Transcriptional and post-transcriptional controls of survivin in cancer cells: novel approaches for cancer treatment.

ABSTRACT: Survivin is a novel member of the inhibitor of apoptosis (IAP) protein family, and its aberrant expression in cancer cells has been shown to be associated with tumorigenesis, cancer progression, radiation/drug resistance and shorter patient survival. Survivin is also expressed in certain human adult tissues and cells, and has been shown to play a role in physiology. Interestingly, targeting survivin for cancer treatment did not show obvious toxicity to normal tissues and cells. This suggests that the mechanism for the regulation and function of survivin may actually be different in cancer cells as compared to normal cells. This review intends to summarize the most important information about the transcriptional and/or post-transcriptional controls of survivin in cancer cells. Further studies along this line may find essential interfaces for the development of novel approaches for cancer therapeutics.

SUBMITTER: Zhang M

PROVIDER: S-EPMC2820411 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Transcriptional and post-transcriptional controls of survivin in cancer cells: novel approaches for cancer treatment.

Zhang M M Yang J J Li F F

Journal of experimental & clinical cancer research : CR 20060901 3

Survivin is a novel member of the inhibitor of apoptosis (IAP) protein family, and its aberrant expression in cancer cells has been shown to be associated with tumorigenesis, cancer progression, radiation/drug resistance and shorter patient survival. Survivin is also expressed in certain human adult tissues and cells, and has been shown to play a role in physiology. Interestingly, targeting survivin for cancer treatment did not show obvious toxicity to normal tissues and cells. This suggests tha ...[more]

PMID: 17167980

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Project description: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.

Dataset Information

Transcriptional and post-transcriptional controls of survivin in cancer cells: novel approaches for cancer treatment.

Publications

Transcriptional and post-transcriptional controls of survivin in cancer cells: novel approaches for cancer treatment.

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