title: 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.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
authors.forename: Jianneng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.|Department of Chemistry, Cleveland State University, Cleveland, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alyamani
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
authors.forename: Kai-Hsiung
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
authors.forename: Ziqi
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.
authors.forename: Marianne
authors.identifier: 0000-0003-3509-2999
authors.initials: M
authors.lastname: Petro
authors.affiliation: Pathology and Laboratory Medicine Institute, Cleveland, United States.
authors.forename: Cristina
authors.initials: C
authors.lastname: Magi-Galluzzi
authors.affiliation: Lank Center of Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland, United States.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Courtney
authors.affiliation: Department of Urology, Glickman Urological and Kidney Institute, Cleveland, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland, United States.|Department of Chemistry, Cleveland State University, Cleveland, United States.|Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland, United States.|Department of Urology, Glickman Urological and Kidney Institute, Cleveland, United States.
authors.forename: Nima
authors.identifier: 0000-0003-1281-3474
authors.initials: N
authors.lastname: Sharifi
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011965:Receptors, Glucocorticoid; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: androgens; biochemistry; cancer biology; glucocorticoids; human; nuclear receptors; prostate cancer; treatment resistance