TY - JOUR TI - Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer AU - Li, Jianneng AU - Alyamani, Mohammad AU - Zhang, Ao AU - Chang, Kai-Hsiung AU - Berk, Michael AU - Li, Zhenfei AU - Zhu, Ziqi AU - Petro, Marianne AU - Magi-Galluzzi, Cristina AU - Taplin, Mary-Ellen AU - Garcia, Jorge A AU - Courtney, Kevin AU - Klein, Eric A AU - Sharifi, Nima A2 - DeBerardinis, Ralph VL - 6 PY - 2017 DA - 2017/02/13 SP - e20183 C1 - eLife 2017;6:e20183 DO - 10.7554/eLife.20183 UR - https://doi.org/10.7554/eLife.20183 AB - 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. KW - prostate cancer KW - androgens KW - glucocorticoids KW - nuclear receptors KW - treatment resistance JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -