Aberrant Tumor Metabolism Enables GR Takeover in Enzalutamide-Resistant Prostate Cancer
Technical Report,01 Jul 2016,30 Jun 2018
Cancer Biology, Lerner Research Institute Cleveland Clinic Foundation Cleveland United States
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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. Here, we show that enzalutamide treatment in models of prostate cancer and patient tissues is accompanied by an ubiquitin E3-ligase, AMFR, mediating loss of 11Beta-hydroxysteroid dehydrogenase-2 11Beta-HSD2, which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11Beta-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. Due to co-localization with hexose-6-phosphate dehydrogenase H6PD, the major generator of endoplasmic reticulum NADPH, 11Beta-HSD1 is predominantly an oxo-reductase in most intact cells but in vivo without the supply of NADPH by H6PD, 11Beta-HSD1 performs the reverse reaction, which results in the inactivation of cortisol. Therefore, I also evaluated whether H6PD plays an important role in ENZ-resistant CRPC. I found that long-term ENZ treatment increased the H6PD protein level and impeded overexpression of H6PD, whereas H6PD knockdown by siRNA accelerated cortisol metabolism in prostate cancer cells. Moreover, I also found that H6PD knockout by CRISPR could reverse the metabolic phenotype of ENZ resistance in LAPC4 cells.
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