A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-α therapy

Chun-Hei Cheung, Xueying Sun, Jagat R. Kanwar, Ji Zhong Bai, Li Ting Cheng, Geoffrey W. Krissansen

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Article number36
JournalCancer Cell International
Volume10
DOIs
Publication statusPublished - 2010 Oct 1

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Prostatic Neoplasms
Apoptosis
Neoplasms
Proteins
Uterine Cervical Neoplasms
Therapeutics
Cell-Penetrating Peptides
Caspase 9
Caspase 8
Affinity Chromatography
Drug Resistance
Caspase 3
Arginine
Cell Survival
Cell Death
Radiotherapy
Western Blotting
Escherichia coli
Drug Therapy
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Cheung, Chun-Hei ; Sun, Xueying ; Kanwar, Jagat R. ; Bai, Ji Zhong ; Cheng, Li Ting ; Krissansen, Geoffrey W. / A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-α therapy. In: Cancer Cell International. 2010 ; Vol. 10.
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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.",
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A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-α therapy. / Cheung, Chun-Hei; Sun, Xueying; Kanwar, Jagat R.; Bai, Ji Zhong; Cheng, Li Ting; Krissansen, Geoffrey W.

In: Cancer Cell International, Vol. 10, 36, 01.10.2010.

Research output: Contribution to journalArticle

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AU - Cheung, Chun-Hei

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