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AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells

Andrea J Detlefsen1, Clementina A Mesaros2,3, Ling Duan2

  • 1Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania.

Cancer Research Communications
|September 29, 2023
PubMed

Insights

Androgen receptor signaling inhibitors (ARSI) resistance in prostate cancer can be overcome. DHEA-S is converted to testosterone (T) via AKR1C3, fueling cancer growth and ARSI resistance.

Area of Science:

  • Oncology
  • Endocrinology
  • Biochemistry

Background:

  • Androgen receptor signaling inhibitors (ARSIs) are crucial for treating castration-resistant prostate cancer (CRPC).
  • However, acquired resistance to ARSIs is a significant clinical challenge, leading to disease relapse and progression.
  • Intratumoral steroidogenesis, particularly via aldo-keto reductase family 1C member 3 (AKR1C3), is implicated in ARSI resistance.

Purpose of the Study:

  • To investigate the role of DHEA-S conversion to testosterone (T) in ARSI resistance in prostate cancer.
  • To identify the key enzyme responsible for this conversion and its clinical relevance.

Main Methods:

  • Utilized prostate cancer cell lines (CWR22PC and DuCaP).
  • Employed stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for androgen measurements.
  • Used short hairpin RNA (shRNA) knockdown and pharmacologic inhibitors to assess AKR1C3 dependence.

Main Results:

  • DHEA-S reservoirs in castrate and post-abiraterone patients were converted to T in prostate cancer cells.
  • This conversion, dependent on AKR1C3, produced sufficient T to stimulate cancer cell growth.
  • AKR1C3 was also found to reduce free DHEA to 5-androstene-3β,17β-diol (5-Adiol), a key precursor to T.

Conclusions:

  • A novel mechanism of ARSI resistance involves AKR1C3-mediated conversion of DHEA-S to T.
  • This pathway, proceeding through 5-Adiol, is active in both primary and metastatic prostate cancer cells.
  • Targeting AKR1C3 may represent a therapeutic strategy to overcome ARSI resistance in prostate cancer.

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