Resistance of prostate cancer (CaP) cells to the next generation anti-androgen, Enzalutamide, may be mediated by a multitude of survival signaling pathways.
In this study we tested whether increased expression of NF-κB2/p52 induces CaP 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 compared to 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 qRT-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 shRNA 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 CaP 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.
Written by:
Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP, Gao AC. Are you the author?
Urology and Cancer Center, University of California at Davis.
Reference: Mol Cancer Ther. 2013 May 22. Epub ahead of print.
doi: 10.1158/1535-7163.MCT-13-0027
PubMed Abstract
PMID: 23699654
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