title: Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Preclinical Research and Development, GTx Inc.; and Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Muralimohan
authors.initials: M
authors.lastname: Yepuru
authors.forename: Zhongzhi
authors.initials: Z
authors.lastname: Wu
authors.forename: Anand
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Feng
authors.initials: F
authors.lastname: Yin
authors.forename: Christina M
authors.initials: CM
authors.lastname: Barrett
authors.forename: Juhyun
authors.initials: J
authors.lastname: Kim
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Steiner
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Ramesh
authors.initials: R
authors.lastname: Narayanan
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000728:Androgens / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009367:Neoplasm Staging; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D034622:RNA Interference; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D013739:Testosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D017430:Prostate-Specific Antigen