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

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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. Prostate 76:491-511, 2016.

Original languageEnglish (US)
Pages (from-to)491-511
Number of pages21
JournalProstate
Volume76
Issue number5
DOIs
StatePublished - Apr 1 2016

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kappa Opioid Receptor
NF-kappa B
Androgen Receptors
Prostatic Hyperplasia
Prostate
Epithelial Cells
Stromal Cells
Prostatic Neoplasms
Ligands
Inflammation
Therapeutics
Type 2 Diabetes Mellitus
Androgens
Cell Survival
Oxidoreductases
Chronic Disease
Phosphotransferases
Cell Line
Growth

Keywords

  • androgen receptor
  • androgen receptor variant 7
  • BPH
  • Inflammation
  • NF-κB

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Austin, D. C., Strand, D. W., Love, H. L., Franco, O. E., Jang, A., Grabowska, M. M., ... Hayward, S. W. (2016). NF-κB and androgen receptor variant expression correlate with human BPH progression. Prostate, 76(5), 491-511. https://doi.org/10.1002/pros.23140

NF-κB and androgen receptor variant expression correlate with human BPH progression. / Austin, David C.; Strand, Douglas W.; Love, Harold L.; Franco, Omar E.; Jang, Alex; Grabowska, Magdalena M.; Miller, Nicole L.; Hameed, Omar; Clark, Peter E.; Fowke, Jay H.; Matusik, Robert J.; Jin, Ren J.; Hayward, Simon W.

In: Prostate, Vol. 76, No. 5, 01.04.2016, p. 491-511.

Research output: Contribution to journalArticle

Austin, DC, Strand, DW, Love, HL, Franco, OE, Jang, A, Grabowska, MM, Miller, NL, Hameed, O, Clark, PE, Fowke, JH, Matusik, RJ, Jin, RJ & Hayward, SW 2016, 'NF-κB and androgen receptor variant expression correlate with human BPH progression', Prostate, vol. 76, no. 5, pp. 491-511. https://doi.org/10.1002/pros.23140
Austin, David C. ; Strand, Douglas W. ; Love, Harold L. ; Franco, Omar E. ; Jang, Alex ; Grabowska, Magdalena M. ; Miller, Nicole L. ; Hameed, Omar ; Clark, Peter E. ; Fowke, Jay H. ; Matusik, Robert J. ; Jin, Ren J. ; Hayward, Simon W. / NF-κB and androgen receptor variant expression correlate with human BPH progression. In: Prostate. 2016 ; Vol. 76, No. 5. pp. 491-511.
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AU - Love, Harold L.

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AU - Grabowska, Magdalena M.

AU - Miller, Nicole L.

AU - Hameed, Omar

AU - Clark, Peter E.

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