Benign prostatic hyperplasia (BPH) is a common, progressive chronic disease. Inflammation is associated with prostatic enlargement and resistance to 5?-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-?B) pathway is linked to both inflammation and ligand-independent prostate cancer progression. Most patients initially respond to 5ARI therapy; however, failure is common. To address why patients fail therapy we used transition zone tissue samples from patients with a wide range of American Urological Association symptom score (AUASS) from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. NF-?B activation and androgen receptor variant (AR-V) expression were quantified. 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-?B activity, AR-FL, and AR-variant 7 (AR-V7). We determined that canonical NF-?B signaling was found to be upregulated in late versus early stage BPH. Elevated expression of AR-V7 was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS. Forced activation of canonical NF-?B 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-?B and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment. To understand why NF-?B and AR-V7 maintained viability within 5ARI treatment we examined the levels of 5?-reductase enzymes (SRD5A1, SRD5A2, SRD5A3). We determined that SRD5A2 is upregulated in more advanced BPH. SRD5A2 was significantly associated with AUASS and patients on a 5ARI. AR-FL and AR-V7 expression increased SRD5A2 expression whereas forced NF-?B activation increased all SRD5A isoforms. In summary, activation of NF-?B and AR-V7 in the prostate is associated with increased disease severity. Increased BPH severity in patients correlates with SRD5A2 expression. De novo synthesis of androgens and AR-V7 expression is inducible in human prostate cells by forced activation of NF-?B. NF-?B and AR-V7 upregulate SRD5A2 resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03172016-154256 |
| Date | 31 March 2016 |
| Creators | Austin, David C. |
| Contributors | Deborah Lannigan, Simon Hayward, Dineo Khabele, Fiona Yull, Ann Richmond |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03172016-154256/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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