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Updated: Apr 17, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer

Chengfei Liu1, Wei Lou1, Yezi Zhu2

  • 1Department of Urology, University of California, Davis, California.

Cancer Research
|February 5, 2015
PubMed

Insights

Acquired resistance to prostate cancer therapies like enzalutamide is a challenge. Targeting the enzyme AKR1C3 and intracrine androgens can overcome this resistance, improving patient survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) treatment improved with enzalutamide and abiraterone.
  • Acquired resistance to these therapies is a significant clinical challenge.
  • Understanding resistance mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the mechanisms underlying enzalutamide resistance in prostate cancer.
  • To identify key molecular targets for overcoming treatment resistance.

Main Methods:

  • Developed enzalutamide-resistant prostate cancer cell lines.
  • Performed global gene-expression analysis and LC/MS analysis of steroid metabolites.
  • Utilized shRNA for gene knockdown and indomethacin for enzyme inhibition.
  • Evaluated treatment efficacy in vitro and in vivo xenograft models.

Main Results:

  • Steroid biosynthesis pathway and AKR1C3 enzyme were significantly upregulated in resistant cells.
  • AKR1C3 expression correlated with advanced prostate cancer and treatment resistance.
  • Inhibition of AKR1C3 resensitized resistant cells to enzalutamide and suppressed tumor growth.
  • Overexpression of AKR1C3 conferred enzalutamide resistance.

Conclusions:

  • AKR1C3 activation is a critical mechanism driving enzalutamide resistance in prostate cancer.
  • Targeting intracrine androgens and AKR1C3 offers a promising strategy to overcome resistance.
  • Combination therapy with enzalutamide and AKR1C3 inhibitors may improve outcomes for advanced prostate cancer patients.

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