Aldo-keto reductase (AKR) 1C3 as an androgen receptor coactivator.

Abstract

100 Background: Castration resistant prostate cancer (CRPC) may occur by several mechanisms including up-regulation of the androgen receptor (AR), coactivators, and steroidogenic enzymes, including AKR1C3. AKR1C3 (type 5 17b-hydroxysteroid dehydrogenase) converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently a major up-regulated gene in CRPC. The objective is to examine the role of AKR1C3 in AR function and CRPC. Methods: AR transactivation studies were performed with GRE-LUC in the presence or absence of AKR1C3 in HEK-293 cells. Gene expression patterns and prostate cancer cell and tumor growth were evaluated in LNCaP and VCaP cells. Molecular studies, including co-immunoprecipitation, chromatin immunoprecipitation and others, were performed to determine AKR1C3 localization and interaction with the AR. Novel small molecule AKR1C3 selective-inhibitors were synthesized and characterized in prostate cancer models. Results: We identified unique AR selective coactivator- and prostate cancer growth-promoting-roles for AKR1C3. AKR1C3 over-expression promotes the growth of both androgen-dependent prostate cancer and CRPC xenografts, with concomitant reactivation of androgen signaling. AKR1C3 interacted with AR in prostate cancer cells and in a human CRPC sample and was recruited to the promoter of an androgen responsive gene, PSA. The coactivator and growth promoting functions of AKR1C3 were inhibited by an AKR1C3-selective competitive inhibitor. Conclusions: AKR1C3 is a novel AR selective coactivator and may represent the first nuclear hormone receptor coactivator that can be pharmacologically targeted.