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Published on: September 6, 2024

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AR-v7 protein expression is regulated by protein kinase and phosphatase

Yinan Li1, Ning Xie1, Martin E Gleave1

  • 1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.

Oncotarget
|September 18, 2015
PubMed

Insights

New findings reveal how protein phosphatase-1 (PP-1) and Akt kinase control androgen receptor variant 7 (AR-v7) expression. This discovery is crucial for understanding castration-resistant prostate cancer (CRPC) progression despite anti-androgen therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Castration-resistant prostate cancer (CRPC) progression is linked to sustained androgen receptor (AR) and its splice variant AR-v7 expression.
  • Next-generation anti-androgens like enzalutamide inhibit AR activity, but AR-v7 remains active, driving CRPC.
  • The molecular mechanisms regulating AR-v7 protein expression are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms controlling AR-v7 protein expression in prostate cancer cells.
  • To investigate the roles of protein phosphatase-1 (PP-1) and Akt kinase in AR-v7 regulation.
  • To understand how these pathways influence AR-v7 activity during anti-androgen therapy.

Main Methods:

  • Utilized multiple prostate cancer cell models.
  • Investigated the activation of protein phosphatase-1 (PP-1) and Akt kinase.
  • Assessed AR phosphorylation status and Mdm2 ubiquitin ligase activation.
  • Examined AR-v7 ubiquitination and protein degradation.

Main Results:

  • Enzalutamide treatment induced differential activation of PP-1 and Akt kinase based on cellular context.
  • The balance between PP-1 and Akt activation determined AR phosphorylation.
  • Activated Mdm2 ligase recognized phosphorylated serine 213 on AR-v7, leading to its ubiquitination and degradation.

Conclusions:

  • PP-1 and Akt kinase play critical roles in regulating AR-v7 protein expression.
  • The PP-1/Akt balance dictates AR-v7 stability and activity.
  • Targeting PP-1 and Akt pathways could offer new therapeutic strategies for CRPC by controlling AR-v7.
Keywords:
AR-v7PP-1 and Aktcastration resistant prostate cancerprotein stabilityserine phosphorylation

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