AKR1C3 Converts Castrate and post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol

Androgen receptor signaling inhibitors (ARSI) are used to treat castration-resistant prostate cancer (CRPC) stop a resurgence of androgen (AR) signaling. Despite early success, patients on ARSIs eventually relapse, develop drug resistance, and succumb the disease. Resistance may occur through intratumoral steroidogenesis mediated by upregulation aldo-keto reductase family 1C member 3 (AKR1C3). Patients treated with leuprolide (castrate) those plus abiraterone (post-Abi) harbor reservoir DHEA-S which could fuel testosterone (T) biosynthesis via AKR1C3 cause cell growth. We demonstrate that concentrations found in castrate post-Abi (i) converted T an AKR1C3-dependent manner cells, (ii) amounts sufficient stimulate observed this primary metastatic lines, CWR22PC DuCaP, respectively. measurements were made stable isotope dilution LC-MS/MS. dependence using short hairpin RNA knockdown pharmacologic inhibitors. also free DHEA is reduced 5-androstene-3β,17β-diol (5-Adiol) major metabolite, suggesting our lines 5-Adiol predominant precursor T. have identified mechanism ARSI resistance common both dependent conversion route catalyzed AKR1C3. Significance: show reservoirs remain after treatment into cells Pharmacologic genetic approaches required for these effects. Furthermore, proceeds 5-Adiol. propose resistance.