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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
07:25

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Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted

Hao Geng1, Changhui Xue1, Janet Mendonca2

  • 1OHSU Knight Cancer Institute, Prostate Cancer Program, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.

Nature Communications
|November 28, 2018
PubMed

Insights

Hypoxia and androgen deprivation therapy (ADT) promote prostate cancer resistance to AR-targeted treatments by altering glucose metabolism via glucose-6-phosphate isomerase (GPI). Inhibiting GPI can overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Androgen receptor (AR)-targeted therapies are crucial for metastatic prostate cancer but face limitations due to adaptive resistance mechanisms.
  • Tumor hypoxia is a known contributor to treatment resistance, yet its precise role in driving AR-independent prostate cancer growth is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which chronic androgen deprivation therapy (ADT) under hypoxic conditions induces adaptive androgen/AR-independence and resistance to AR-targeted therapy.
  • To investigate the role of glucose-6-phosphate isomerase (GPI) in mediating this resistance and to evaluate GPI inhibition as a therapeutic strategy.

Main Methods:

  • Investigated the interplay between chronic ADT, hypoxia, and AR signaling in prostate cancer.
  • Utilized molecular biology techniques to assess the transcriptional regulation of GPI by AR under hypoxic conditions.
  • Examined the metabolic shift from the pentose phosphate pathway (PPP) to glycolysis.
  • Evaluated the efficacy of GPI inhibition in vitro and in vivo models of enzalutamide resistance.

Main Results:

  • Chronic ADT combined with hypoxia induces adaptive androgen/AR-independence, leading to resistance against enzalutamide.
  • AR represses GPI transcription in hypoxia; AR inhibition restores and increases GPI levels.
  • GPI redirects glucose flux to glycolysis, maintaining energy homeostasis and reducing enzalutamide's growth inhibitory effects.
  • Inhibition of GPI effectively overcomes therapy resistance in vitro and enhances enzalutamide efficacy in vivo.

Conclusions:

  • The study identifies a novel mechanism of therapy resistance in prostate cancer involving GPI-mediated metabolic adaptation under hypoxia and ADT.
  • Targeting GPI represents a promising strategy to overcome resistance to AR-targeted therapies in patients with metastatic prostate cancer, particularly in hypoxic tumors.

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