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Mol Cancer Ther. 2016 Sep;15(9):2107-18. doi: 10.1158/1535-7163.MCT-16-0241. Epub 2016 Jul 7.

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer.

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Department of Biochemistry, Purdue University, West Lafayette, Indiana.
Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.
Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
Department of Urology, Case Western Reserve University, Cleveland, Ohio.
Department of Biochemistry, Purdue University, West Lafayette, Indiana. Center for Cancer Research, Purdue University, West Lafayette, Indiana.


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. Mol Cancer Ther; 15(9); 2107-18.

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Conflict of interest statement

of Potential Conflicts of Interest: No potential conflicts of interest are disclosed by the authors.

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