NF-κB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants

Mol Cancer Ther. 2013 Aug;12(8):1629-37. doi: 10.1158/1535-7163.MCT-13-0027. Epub 2013 May 22.

Abstract

Resistance of prostate cancer cells to the next-generation antiandrogen enzalutamide may be mediated by a multitude of survival signaling pathways. In this study, we tested whether increased expression of NF-κB2/p52 induces prostate cancer cell resistance to enzalutamide and whether this response is mediated by aberrant androgen receptor (AR) activation and AR splice variant production. LNCaP cells stably expressing NF-κB2/p52 exhibited higher survival rates than controls when treated with enzalutamide. C4-2B and CWR22Rv1 cells chronically treated with enzalutamide were found to express higher levels of NF-κB2/p52. Downregulation of NF-κB2/p52 in CWR22Rv1 cells chronically treated with enzalutamide rendered them more sensitive to cell growth inhibition by enzalutamide. Analysis of the expression levels of AR splice variants by quantitative reverse transcription PCR and Western blotting revealed that LNCaP cells expressing p52 exhibit higher expression of AR splice variants. Downregulation of expression of NF-κB2/p52 in VCaP and CWR22Rv1 cells by short hairpin RNA abolished expression of splice variants. Downregulation of expression of either full-length AR or the splice variant AR-V7 led to an increase in sensitivity of prostate cancer cells to enzalutamide. These results collectively demonstrate that resistance to enzalutamide may be mediated by NF-κB2/p52 via activation of AR and its splice variants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing
  • Androgen Antagonists / pharmacology*
  • Benzamides
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Genetic Variation
  • Humans
  • Male
  • NF-kappa B p52 Subunit / genetics*
  • NF-kappa B p52 Subunit / metabolism
  • Nitriles
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / pharmacology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism

Substances

  • Androgen Antagonists
  • Benzamides
  • NF-kappa B p52 Subunit
  • Nitriles
  • Receptors, Androgen
  • Phenylthiohydantoin
  • enzalutamide