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Androgen glucuronidation: an unexpected target for androgen deprivation therapy, with prognosis and diagnostic

Laurent Grosse1, Sophie Pâquet, Patrick Caron

  • 1Authors' Affiliations: Laboratory of Molecular Pharmacology, CHU-Québec Research Centre and Faculty of Pharmacy, CHU-Québec Research Centre and Faculty of Medicine, Laval University, Québec; and Vancouver Prostate Centre at VGH, University of British Columbia, Vancouver, British Columbia, Canada.

Cancer Research
|October 15, 2013
PubMed

Insights

Androgen deprivation therapy increases androgen metabolism in prostate cancer cells by upregulating UGT2B15 and UGT2B17 enzymes. This finding suggests UGT2B15 and UGT2B17 could be therapeutic targets or markers for prostate cancer treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Androgen deprivation therapy (ADTh) is a primary treatment for prostate cancer, but resistance mechanisms are not fully understood.
  • Androgen glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes UGT2B15 and UGT2B17 is a key androgen inactivation pathway in prostate cancer cells.

Purpose of the Study:

  • To investigate the impact of ADTh on androgen glucuronidation.
  • To assess the potential clinical utility of UGT2B15 and UGT2B17 in prostate cancer prognosis or therapy.

Main Methods:

  • Evaluated UGT2B15 and UGT2B17 expression in prostate cancer specimens from treated and untreated patients.
  • Assessed UGT2B15 and UGT2B17 expression and activity in prostate cancer cell lines exposed to antiandrogens.
  • Confirmed the role of the androgen receptor (AR) in regulating UGT expression using AR-deficient cells.

Main Results:

  • ADTh significantly increased UGT2B15 and UGT2B17 protein levels in prostate tissue.
  • Antiandrogens stimulated UGT2B15 and UGT2B17 expression and activity in prostate cancer cell lines.
  • AR antagonism of UGT2B attenuated the antiproliferative effects of AR antagonists in AR-deficient cells.

Conclusions:

  • ADTh stimulates local androgen metabolism in prostate cells via UGT2B15 and UGT2B17.
  • UGT2B15 and UGT2B17 represent potential drug targets and/or biomarkers for ADTh responsiveness and maintenance in prostate cancer.

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