NF-kB2/p52 induces resistance to enzalutamide in prostate cancer

Role of androgen receptor and its variants

Nagalakshmi Nadiminty, Ramakumar Tummala, Chengfei Liu, Joy Yang, Wei Lou, Christopher P Evans, Allen C Gao

Research output: Contribution to journalArticle

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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-kB2/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-kB2/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 NFkB2/ p52. Downregulation of NF-kB2/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 NFkB2/ 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-kB2/p52 via activation of AR and its splice variants. Mol Cancer Ther; 12(8); 1629-37.

Original languageEnglish (US)
Pages (from-to)1629-1637
Number of pages9
JournalMolecular Cancer Therapeutics
Volume12
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Androgen Receptors
Prostatic Neoplasms
Down-Regulation
MDV 3100
Androgen Antagonists
Small Interfering RNA
Reverse Transcription
Western Blotting
Polymerase Chain Reaction
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

NF-kB2/p52 induces resistance to enzalutamide in prostate cancer : Role of androgen receptor and its variants. / Nadiminty, Nagalakshmi; Tummala, Ramakumar; Liu, Chengfei; Yang, Joy; Lou, Wei; Evans, Christopher P; Gao, Allen C.

In: Molecular Cancer Therapeutics, Vol. 12, No. 8, 08.2013, p. 1629-1637.

Research output: Contribution to journalArticle

Nadiminty, Nagalakshmi ; Tummala, Ramakumar ; Liu, Chengfei ; Yang, Joy ; Lou, Wei ; Evans, Christopher P ; Gao, Allen C. / NF-kB2/p52 induces resistance to enzalutamide in prostate cancer : Role of androgen receptor and its variants. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 8. pp. 1629-1637.
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