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

Abstract

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 recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions. CONCLUSION 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.

Expression of Steroid and Peptide Hormone Receptors, Metabolic Enzymes and Emt-Related Genes in Prostate Tumors in Relation to the Presence of the Tmprss2/Erg Fusion

“…Noteworthy, in adenomas we have detected the highest SRD5A2 RE levels. It is known that increased SRD5A2 in adenomas provokes hyperplasia extension through NF-kB and AR isoform 7 conferring 5α-reductase inhibitors resistance [26]. From other hand decreased levels of SRD5A2 in adenocarcinomas is associated with the enhanced cell migration and invasion [7].…”

Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression

“…Although multiple mechanisms have been proposed to explain escape from ADT (such as AR amplification, modification of the AR by point mutations or phosphorylation, and changes in AR co-activators), recent studies have demonstrated that the elevated expression of ARVs is an important driving force in developing CRPC [ 1 – 5 ]. We have shown that activation of NF-κB signaling increases ARVs (AR-V7) in benign prostatic tissue [ 8 ], PC [ 9 ], and NF-κB/AR-V7 increases expression of steroid-5α-reductase type II, the enzyme which converts testosterone to dihydrotestosterone, the most active androgen [ 61 ]. In support of our reports, Nadiminty et al demonstrated that NF-κB regulates expression of ARVs in CRPC [ 10 ].…”

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

“…Castration induces cell death and inflammation in the prostate, which needs to be controlled by macrophages [ 42 ], but these immunosuppressive myeloid cells can also contribute to the development of castration-resistant prostate cancer [ 43 ]. Noteworthy, induction of endogenous androgen biosynthesis in prostate cancer cells is at least partially driven by NF-κB, and might thus also be promoted by inflammation induced by castration [ 44 ].…”