title: Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer.
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. Mol Cancer Ther; 15(9); 2107-18. ©2016 AACR.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Elia
authors.initials: E
authors.lastname: Farah
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.
authors.forename: Sukumar
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Urology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia.
authors.forename: James
authors.initials: J
authors.lastname: Larner
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana. Center for Cancer Research, Purdue University, West Lafayette, Indiana. liu8@purdue.edu.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1