Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 13, 2017
- Source ID
- 10.7554/elife.20183
Entities
People
- Ao Zhang
- Cristina Magi-galluzzi
- Eric A Klein
- Jianneng Li
- Jorge A. Garcia
- Kai-hsiung Chang
- Kevin Courtney
- Marianne Petro
- Mary-ellen Taplin
- Michael Berk
- Mohammad Alyamani
- Nima Sharifi
- Zhenfei Li
- Ziqi Zhu
Organizations
- American Cancer Society
- Cleveland State University
- Harvard Medical School
- Howard Hughes Medical Institute
- National Cancer Institute
- Prostate Cancer Foundation
- United States Department of Defense
- University of Texas at Austin