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Crystal Structure of the N-terminal Domain of Ryanodine Receptor from Plutella xylostella
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Published on: November 30, 2018

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Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

Jun Dong1,2, Zeyu Wu1,3, Dan Wang1

  • 1Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Molecular Cancer Therapeutics
|October 10, 2018
PubMed

Insights

Heat shock protein 70 (Hsp70) is identified as a novel cofactor for the androgen receptor (AR) N-terminal domain. Inhibiting Hsp70 shows potential for treating enzalutamide-resistant prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Androgen receptor (AR) signaling is crucial in prostate cancer progression, including castration-resistant prostate cancer (CRPC).
  • Current AR inhibitors target the ligand-binding domain (LBD), necessitating new therapeutic strategies targeting other AR domains.
  • The N-terminal domain (NTD) of AR interacts with cofactors that regulate its activity.

Purpose of the Study:

  • To identify novel cofactors interacting with the AR NTD.
  • To investigate the role of identified cofactors in AR signaling and prostate cancer proliferation.
  • To evaluate Hsp70 as a potential therapeutic target for enzalutamide-resistant CRPC.

Main Methods:

  • Proteomic analysis using a pull-down approach to identify AR NTD-interacting cofactors.
  • siRNA and small molecule inhibitors to assess Hsp70's role in AR expression and transactivation.
  • Luciferase assays to evaluate Hsp70's requirement for AR transactivation, including LBD-mutant AR.
  • Clonogenic assays to assess the efficacy of Hsp70 inhibition in enzalutamide-resistant prostate cancer cells.

Main Results:

  • Heat shock protein 70 (Hsp70) was identified as a novel cofactor interacting with the AR NTD.
  • Hsp70 inhibition significantly reduced endogenous AR expression and transactivation.
  • Hsp70 was essential for the transactivation of AR mutants lacking the LBD.
  • Hsp70 inhibition, alone or with enzalutamide, suppressed the proliferation of enzalutamide-resistant CRPC cells (22Rv1).

Conclusions:

  • Hsp70 is a critical cofactor for AR NTD function in prostate cancer cells.
  • Targeting Hsp70 represents a promising therapeutic strategy for overcoming enzalutamide resistance in CRPC.
  • Hsp70 inhibition offers a potential new avenue for treating advanced prostate cancer.

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