NF-κ B and Androgen Receptor Variant 7 Induce Expression of SRD 5 A Isoforms and Confer 5 ARI Resistance

BACKGROUND—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. METHODS—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. RESULTS—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 Correspondence to: Simon W. Hayward, PhD, Department of Cancer Biology, NorthShore University HealthSystem Research Institute, 1001 University Place, Evanston, IL 60201. shayward@northshore.org. Present address of Douglas W. Strand is Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Conflicts of interest: The authors have nothing to disclose. HHS Public Access Author manuscript Prostate. Author manuscript; available in PMC 2016 August 01. Published in final edited form as: Prostate. 2016 August ; 76(11): 1004–1018. doi:10.1002/pros.23195. A uhor M anscript

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