Steroidogenic Enzyme AKR1C3 Is a Novel Androgen Receptor-Selective Coactivator that Promotes Prostate Cancer Growth

Abstract

Purpose: Castration-resistant prostate cancer (CRPC) may occur by several mechanisms including the upregulation of androgen receptor (AR), coactivators, and steroidogenic enzymes, including aldo keto reductase 1C3 (AKR1C3). AKR1C3 converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently the major upregulated gene in CRPC. The studies in the manuscript were undertaken to examine the role of AKR1C3 in AR function and CRPC.Experimental Design: LNCaP cells stably transfected with AKR1C3 and VCaP cells endogenously expressing AKR1C3 were used to understand the effect of AKR1C3 on prostate cancer cell and tumor growth in nude mice. Chromatin immunoprecipitation, confocal microscopy, and co-immunoprecipitation studies were used to understand the recruitment of AKR1C3, intracellular localization of AKR1C3 and its interaction with AR in cells, tumor xenograft, and in Gleason sum 7 CRPC tissues. Cells were transiently transfected for AR transactivation. Novel small-molecule AKR1C3-selective inhibitors were synthesized and characterized in androgen-dependent prostate cancer and CRPC models.Results: We identified unique AR-selective coactivator-and prostate cancer growth-promoting roles for AKR1C3. AKR1C3 overexpression 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, xenografts, and in human CRPC samples and was recruited to the promoter of an androgen-responsive gene. The coactivator and growth-promoting functions of AKR1C3 were inhibited by an AKR1C3-selective competitive inhibitor.Conclusions: AKR1C3 is a novel AR-selective enzymatic coactivator and may represent the first of more than 200 known nuclear hormone receptor coactivators that can be pharmacologically targeted.

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

“…Notably, it was recently reported that AKR1C3 (WT or CI mutant) could function as an AR co-activator (52), another example of a catalytically independent role of AKR1C3 on AR activity. Therefore, identification of mechanisms underlying the noncatalytic function of AKR1C3 may provide new targets for development of novel AKR1C3 inhibitors that complement inhibitors targeting AKR1C3 catalytic activity as potential CRPC therapy.…”

Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC)

“…GTX-560, a potent competitive inhibitor of AKR1C3, revealed for the first time that this compound could block the hitherto unrecognized AR co-activator function of AKR1C3 suggesting that the compound would have added benefit in the treatment of CRPC patients [74]. GTx-560 was also found to have antitumor activity in prostate cancer cell xenograft models of CRPC.…”

Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review

“…Isoquinolines represented by the lead compound GTX-560 27 not only act as competitive inhibitors of AKR1C3 but also block its AR coactivator function which was previously unknown [58]. The isoquinolines were claimed in patents WO2013142390 and WO2014039820A1 filed by GTx-Therapeutics.…”