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Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer

Masis Isikbay1, Kristen Otto, Steven Kregel

  • 1Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 S. Maryland Ave. MC 2115, Chicago, IL, 60637, USA.

Hormones & Cancer
|March 12, 2014
PubMed

Insights

Glucocorticoid receptor (GR) activation promotes castrate-resistant prostate cancer (CRPC) progression by increasing cell survival via SGK1. Inhibiting GR or SGK1 may enhance androgen receptor (AR)-directed therapies for CRPC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Castrate-resistant prostate cancer (CRPC) poses a significant challenge due to acquired resistance to androgen receptor (AR)-directed therapies.
  • Glucocorticoid receptor (GR) and AR share transcriptional targets, including anti-apoptotic genes like SGK1.
  • Increased GR expression is observed in some prostate cancers after androgen deprivation therapy.

Purpose of the Study:

  • To investigate whether GR activation contributes to resistance against AR-directed therapy in prostate cancer.
  • To elucidate the role of GR and SGK1 in the progression of CRPC.

Main Methods:

  • Utilized prostate cancer cell lines (CWR-22Rv1, LAPC4) treated with androgens, AR antagonists, GR agonists/antagonists, and SGK1 inhibitors.
  • Employed GR-knockdown and SGK1-overexpressing cell lines in vitro and in vivo xenograft models.
  • Assessed tumor cell viability, gene expression (SGK1, MKP1/DUSP1), and PSA secretion.

Main Results:

  • GR activation counteracted the effects of the AR antagonist MDV3100 on cell viability.
  • GR activation increased PSA secretion and induced SGK1 and MKP1/DUSP1 gene expression.
  • GR depletion delayed castrate-resistant tumor formation, while SGK1 overexpression accelerated it in vivo.

Conclusions:

  • Increased GR expression and activity contribute to tumor cell viability and progression in CRPC.
  • GR-regulated SGK1 expression plays a key role in mediating enhanced prostate cancer cell survival.
  • Inhibiting GR and/or SGK1 could be a valuable strategy as an adjunct to AR blockade for CRPC treatment.

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