TY - JOUR
T1 - 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
N1 - Funding Information:
We thank David Schumick for help with the illustration in Figure 1. We thank Mike Brown for helpful comments. This work has been supported in part by funding to NS from a Howard Hughes Medical Institute Physician-Scientist Early Career Award, a Prostate Cancer Foundation Challenge Award, an American Cancer Society Research Scholar Award (12–038-01-CCE), grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289).
Publisher Copyright:
© Li et al.
PY - 2017/2/13
Y1 - 2017/2/13
N2 - 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.
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.
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U2 - 10.7554/eLife.20183
DO - 10.7554/eLife.20183
M3 - Article
C2 - 28191869
AN - SCOPUS:85013498415
SN - 2050-084X
VL - 6
JO - eLife
JF - eLife
M1 - e20183
ER -