Cotargeting HSP90 and its client proteins for treatment of prostate cancer

Long Chen, Jie Li, Elia Farah, Sukumar Sarkar, Nihal Ahmad, Sanjay Gupta, James Larner, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) reactivation is responsible for the recurrence of prostate cancer after ADT. Thus, targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSP) are chaperones that modify stability and activity of their client proteins. HSP90, a major player in the HSP family, regulates stability 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 prostate cancer. Herein, we show that cotreatment of prostate cancer 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 cotargeting 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 cotargeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC.

Original languageEnglish
Pages (from-to)2107-2118
Number of pages12
JournalMolecular Cancer Therapeutics
Volume15
Issue number9
DOIs
StatePublished - Sep 2016

Bibliographical note

Publisher Copyright:
© 2016 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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