Aberrant Tumor Metabolism 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. 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 11-hydroxysteroid dehydrogenase-2 (11-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11-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. I also investigated 11-HSD1 in the context of ENZ resistance, and found its expression level was not altered. Due to co-localization with hexose 6 phosphate dehydrogenase (H6PD), the major generator of endoplasmic reticulum NADPH, 11-HSD1 is predominantly an oxo-reductase in most intact cells, but in vivo without the supply of NADPH by H6PD, 11-HSD1 performs the reverse reaction, which results in the inactivation of cortisol. Hence, we hypothesize that long-term ENZ treatment increases H6PD, leading to enhanced 11-HSD1 oxo-reductase activity and collaboration with the downregulated 11-HSD2 activity impedes cortisol metabolism and lengthens GR activation to sustain tumor growth despite AR blockade. In my upcoming funding year, I will confirm whether H6PD plays an important role in ENZ-resistant prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2017
- Accession Number
- AD1050369
Entities
People
- Jianneng Li