Benign prostatic hyperplasia (BPH) is a common, chronic progressive disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand-independent prostate cancer progression.
NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. To further investigate these pathways, human prostatic stromal and epithelial cell lines were transduced with constitutively active or kinase dead forms of IKK2 to regulate canonical NF-κB activity. The effects on AR full length (AR-FL) and androgen-independent AR-V expression as well as cellular growth and differentiation were assessed.
Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR variants, was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS and TRUS volume. Forced activation of canonical NF-κB in human prostatic epithelial and stromal cells resulted in elevated expression of both AR-FL and AR-V7, with concomitant ligand-independent activation of AR reporters. Activation of NF-κB and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment.
Activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy. Prostate © 2015 Wiley Periodicals, Inc.
The Prostate. 2015 Dec 28 [Epub ahead of print]
David C Austin, Douglas W Strand, Harold L Love, Omar E Franco, Alex Jang, Magdalena M Grabowska, Nicole L Miller, Omar Hameed, Peter E Clark, Jay H Fowke, Robert J Matusik, Ren J Jin, Simon W Hayward
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Surgery, NorthShore University HealthSystem Research Institute, Evanston, Illinois. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. , Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.