Targeting the Hsp40/Hsp70 chaperone axis as a novel strategy to treat aastration-resistant prostate cancer

Michael A. Moses, Yeong Sang Kim, Genesis M. Rivera-Marquez, Nobu Oshima, Matthew J. Watson, Kristin E. Beebe, Catherine Wells, Sunmin Lee, Abbey D. Zuehlke, Hao Shao, William E. Bingman, Vineet Kumar, Sanjay V. Malhotra, Nancy L. Weigel, Jason E. Gestwicki, Jane B. Trepel, Leonard M. Neckers

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy. Significance: These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy.

Original languageEnglish (US)
Pages (from-to)4022-4035
Number of pages14
JournalCancer Research
Volume78
Issue number14
DOIs
StatePublished - Jul 15 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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