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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Co-targeting HSP90 and its client proteins for treatment of prostate cancer

Long Chen, Jie Li, Elia Farah, Sukumar Sarkar, Nihal Ahmad, Sanjay Gupta, James Larner and Xiaoqi Liu
Long Chen
Department of Biochemistry, Purdue University
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Jie Li
Department of Biochemistry, Purdue University
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Elia Farah
Department of Biochemistry, Purdue University
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Sukumar Sarkar
Department of Radiation Oncology, University of Virginia
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Nihal Ahmad
Department of Dermatology, University of Wisconsin
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Sanjay Gupta
Department of Urology, Case Western Reserve University
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James Larner
Department of Radiation Oncology, University of Virginia
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Xiaoqi Liu
Department of Biochemistry, Purdue University
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  • For correspondence: liu8@purdue.edu
DOI: 10.1158/1535-7163.MCT-16-0241
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Abstract

Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer (PCa) when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) re-activation is responsible for the recurrence of PCa after ADT. Thus targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSPs) are chaperones that modify stability and activity of their client proteins. HSP90, a major player of the HSP family, regulates stabilities of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events. Further, HSP90 is overexpressed in different cancers, including PCa. Herein, we show that co-treatment of PCa with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that co-targeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that co-targeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC.

  • Received April 21, 2016.
  • Revision received June 9, 2016.
  • Accepted June 26, 2016.
  • Copyright ©2016, American Association for Cancer Research.
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Published OnlineFirst July 7, 2016
doi: 10.1158/1535-7163.MCT-16-0241

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Co-targeting HSP90 and its client proteins for treatment of prostate cancer
Long Chen, Jie Li, Elia Farah, Sukumar Sarkar, Nihal Ahmad, Sanjay Gupta, James Larner and Xiaoqi Liu
Mol Cancer Ther July 7 2016 DOI: 10.1158/1535-7163.MCT-16-0241

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Co-targeting HSP90 and its client proteins for treatment of prostate cancer
Long Chen, Jie Li, Elia Farah, Sukumar Sarkar, Nihal Ahmad, Sanjay Gupta, James Larner and Xiaoqi Liu
Mol Cancer Ther July 7 2016 DOI: 10.1158/1535-7163.MCT-16-0241
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Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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