| Abstract: |
Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" stage that results in renewed growth and spread of the cancer. Both nuclear factor-κB (NF-κB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-κB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-κB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-κB signaling in vivo by the absence of the IκBα inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-κB pathway was activated in the ARR 2PB-myc-PAI (Hi-myc) mouse prostate by crossbreeding into a IκBα+/- haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-κB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating action. Thus, the NF-κB pathway may be a potential target for therapy against androgen-independent prostate cancer. © 2008 American Association for Cancer Research. |
| Keywords: |
immunohistochemistry; signal transduction; protein expression; human cell; genetics; androgen; disease course; cancer growth; nonhuman; drug targeting; neoplasm; cell proliferation; mouse; animal; metabolism; mouse mutant; animals; mice; mice, knockout; animal tissue; reverse transcription polymerase chain reaction; apoptosis; embryo; animal experiment; animal model; immunoglobulin enhancer binding protein; genetic transcription; cell differentiation; transcription, genetic; enzyme activation; in vitro study; pathology; tumor cells, cultured; prediction; physiology; cancer hormone therapy; prostate cancer; prostatic neoplasms; tissue section; gene expression regulation; cancer inhibition; blotting, western; gene expression regulation, neoplastic; cancer regression; cell culture; nude mouse; messenger rna; reverse transcriptase polymerase chain reaction; rna, messenger; disease progression; prostate tumor; nf-kappa b; western blotting; carcinoma; prostate epithelium; androgen receptor; prostate adenocarcinoma; cell nucleus; castration; receptors, androgen; hormonal regulation; anchorage independent growth; androgens; i kappa b kinase; cell strain lncap; androgen blood level; neoplasms, hormone-dependent; carcinoma, neuroendocrine; ar protein, human; neurosecretory cell; cross breeding; i-kappa b kinase; i kappa b alpha; i kappa b kinase inhibitor
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