Author:
Cheung Chun Hei Antonio,Sun Xueying,Kanwar Jagat R,Bai Ji-Zhong,Cheng LiTing,Krissansen Geoffrey W
Abstract
Abstract
Background
Survivin is a member of the inhibitor-of-apoptosis (IAP) family which is widely expressed by many different cancers. Overexpression of survivin is associated with drug resistance in cancer cells, and reduced patient survival after chemotherapy and radiotherapy. Agents that antagonize the function of survivin hold promise for treating many forms of cancer. The purpose of this study was to investigate whether a cell-permeable dominant-negative survivin protein would demonstrate bioactivity against prostate and cervical cancer cells grown in three dimensional culture.
Results
A dominant-negative survivin (C84A) protein fused to the cell penetrating peptide poly-arginine (R9) was expressed in E. coli and purified by affinity chromatography. Western blot analysis revealed that dNSurR9-C84A penetrated into 3D-cultured HeLa and DU145 cancer cells, and a cell viability assay revealed it induced cancer cell death. It increased the activities of caspase-9 and caspase-3, and rendered DU145 cells sensitive to TNF-α via by a mechanism involving activation of caspase-8.
Conclusions
The results demonstrate that antagonism of survivin function triggers the apoptosis of prostate and cervical cancer cells grown in 3D culture. It renders cancer cells sensitive to the proapoptotic affects of TNF-α, suggesting that survivin blocks the extrinsic pathway of apoptosis. Combination of the biologically active dNSurR9-C84A protein or other survivin antagonists with TNF-α therapy warrants consideration as an approach to cancer therapy.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Reference37 articles.
1. Zaffaroni N, Daidone MG: Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist Updat. 2002, 5: 65-72. 10.1016/S1368-7646(02)00049-3.
2. Cheung CH, Chen HH, Kuo CC, Chang CY, Coumar MS, Hsieh HP, Chang JY: Survivin counteracts the therapeutic effect of microtubule de-stabilizers by stabilizing tubulin polymers. Mol Cancer. 2009, 8: 43-10.1186/1476-4598-8-43.
3. Moriai R, Tsuji N, Moriai M, Kobayashi D, Watanabe N: Survivin plays as a resistant factor against tamoxifen-induced apoptosis in human breast cancer cells. Breast Cancer Res Treat. 2009, 117: 261-271. 10.1007/s10549-008-0164-5.
4. Jiang G, Ren B, Xu L, Song S, Zhu C, Ye F: Survivin may enhance DNA double-strand break repair capability by up-regulating Ku70 in human KB cells. Anticancer Res. 2009, 29: 223-228.
5. Nakamura M, Tsuji N, Asanuma K, Kobayashi D, Yagihashi A, Hirata K, Torigoe T, Sato N, Watanabe N: Survivin as a predictor of cis-diamminedichloroplatinum sensitivity in gastric cancer patients. Cancer Sci. 2004, 95: 44-51. 10.1111/j.1349-7006.2004.tb03169.x.
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