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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling

Neetu Saxena1, Eliana Beraldi1, Ladan Fazli1

  • 1Vancouver Prostate Centre, Vancouver, BC, Canada.

EMBO Molecular Medicine
|March 12, 2021
PubMed

Insights

Androgen receptor pathway inhibition triggers adaptive responses in prostate cancer (PCa) by altering energy metabolism. Targeting the androgen receptor (AR) with Hsp27 sensitizes PCa cells to treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Treatment-induced adaptive pathways promote castration-resistant prostate cancer (PCa) by reactivating the androgen receptor (AR).
  • Acute adaptive responses orchestrating energy metabolism shifts after AR pathway inhibition (ARPI) are not well-defined.
  • Succinate dehydrogenase (SDH), a TCA cycle enzyme, exhibits tumor suppressor activity and is rapidly altered post-ARPI.

Purpose of the Study:

  • To investigate acute adaptive responses in energy metabolism following ARPI in prostate cancer.
  • To elucidate the role of succinate dehydrogenase (SDH) in AR reactivation and castration-resistant PCa.
  • To explore Hsp27 as a co-targeting strategy with ARPI.

Main Methods:

  • Analysis of SDH activity and its regulation by AR.
  • Measurement of succinate levels and its downstream effects.
  • Investigation of the CaMKK2/AMPK/p38 signaling axis and Hsp27 phosphorylation.
  • Validation in prostatectomy tissue microarrays and patient-derived xenografts.
  • In vitro and in vivo studies co-targeting AR and Hsp27.

Main Results:

  • AR directly regulates SDH subunit transcription via androgen response elements (AREs).
  • ARPI acutely suppresses SDH activity, causing oncometabolite succinate accumulation.
  • Succinate triggers calcium release, leading to Hsp27 phosphorylation and enhanced AR stabilization via the p-CaMKK2/p-AMPK/p-p38 axis.
  • This adaptive pathway is active in clinical prostatectomy tissues and xenografts.
  • Co-targeting AR with Hsp27 blocks this adaptive response, sensitizing PCa cells to ARPI.

Conclusions:

  • ARPI induces an adaptive metabolic shift involving SDH suppression and succinate accumulation.
  • Succinate-mediated Hsp27 activation promotes AR reactivation and castration resistance.
  • Co-targeting AR and Hsp27 represents a promising strategy to overcome treatment resistance in prostate cancer.
Keywords:
Androgen receptorHsp27prostate cancersuccinatesuccinate dehydrogenase

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