title: NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.
abstract: Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.
  
  
  
  Tissue was collected from "Surgical" patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from "Incidental" patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.
  
  
  
  SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.
  
  
  
  Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: David C
authors.initials: DC
authors.lastname: Austin
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Strand
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Love
authors.affiliation: Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, Illinois.
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Grabowska
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Miller
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Omar
authors.initials: O
authors.lastname: Hameed
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clark
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ren J
authors.initials: RJ
authors.lastname: Jin
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, Illinois.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics* / Q000502:physiology; D058891:5-alpha Reductase Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D004351:Drug Resistance; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D059411:Lower Urinary Tract Symptoms / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009919:Orchiectomy; D011467:Prostate / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D064129:Prostatic Neoplasms, Castration-Resistant; D011944:Receptors, Androgen / Q000502:physiology*; D013739:Testosterone / Q000096:biosynthesis; D017211:Treatment Failure; D015854:Up-Regulation
chemical_list: D058891:5-alpha Reductase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D011944:Receptors, Androgen; D013739:Testosterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human
keywords: BPH; androgen receptor; androgen receptor variant 7; inflammation; p65