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Elife. 2017 Feb 13;6. pii: e20183. doi: 10.7554/eLife.20183.

Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer.

Author information

1
Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
2
Department of Chemistry, Cleveland State University, Cleveland, United States.
3
Pathology and Laboratory Medicine Institute, Cleveland, United States.
4
Lank Center of Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
5
Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland, United States.
6
Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
7
Department of Urology, Glickman Urological and Kidney Institute, Cleveland, United States.

Abstract

Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

KEYWORDS:

androgens; biochemistry; cancer biology; glucocorticoids; human; nuclear receptors; prostate cancer; treatment resistance

Comment in

PMID:
28191869
PMCID:
PMC5305204
DOI:
10.7554/eLife.20183
[Indexed for MEDLINE]
Free PMC Article

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