NF‐κB and androgen receptor variant expression correlate with human BPH progression

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

NF‐κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance

“…In prostate cancer SRD5A1 and SRD5A2 predict biochemical recurrence and reduced efficacy of androgen deprivation therapy . In a previous study , we demonstrated that both activation of NF‐κB and subsequent induction of AR‐V7, contributed to resistance to a 5ARI. Here we examine whether the induction of SRD5A expression could also be a player in this phenomenon.…”

“…Expression of AR‐V7 is predictive of resistance to Enzalutamide and abiraterone acetate in prostate cancer patients . Gao has reported that AR‐Vs can be produced in response to the non‐canonical NF‐κB pathway, and we have shown that AR‐Vs can be induced by the canonical NF‐κB pathway . Currently, however there is not an established mechanistic link between NF‐κB and resistance to 5ARI therapy in BPH.…”

“…To clarify the underlying molecular processes, a series of in vitro experiments was performed to examine the effects of NF‐κB on SRD5A levels. We have previously shown that NF‐κB is upregulated in the Surgical BPH patient samples and that NF‐κB activation can induce AR‐FL and AR‐V7 expressions . Here, we wanted to determine whether NF‐κB activation could affect SRD5A expression in benign human prostatic cell lines.…”

Caffeic acid phenethyl ester guards against benign prostate hypertrophy in rats: Role of IGF‐1R/protein kinase‐B (Akt)/β‐catenin signaling

“…This gains support by the work of Austin et al . , who indicated an upregulation of NF‐κB signaling in prostate tissue specimens from patients with BPH. Co‐treatment with CAPE opposed testosterone‐induced elevation in the level of TNF‐α and NF‐κB activity, which indicated the suppression of inflammation.…”

Review of Prostate Anatomy and Embryology and the Etiology of Benign Prostatic Hyperplasia

“…50 In addition inflammation, activation of NF-κB signaling and subsequent and expression of constitutively active androgen receptor variant 7 have been shown to correlate with both BPH progression and prostate volume. 51 Stromal nodules of BPH contain increased T and B lymphocytes. 52 Elevated levels of inflammatory cells have also been detected in the interstitium and surrounding epithelial glands of human BPH.…”