title: NF-kappaB regulates androgen receptor expression and prostate cancer growth.
abstract: Prostate cancers that progress during androgen-deprivation therapy often overexpress the androgen receptor (AR) and depend on AR signaling for growth. In most cases, increased AR expression occurs without gene amplification and may be due to altered transcriptional regulation. The transcription factor nuclear factor (NF)-kappaB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways. NF-kappaB is an important determinant of prostate cancer clinical biology, and therefore we investigated its role in the regulation of AR expression. We found that NF-kappaB expression in prostate cancer cells significantly increased AR mRNA and protein levels, AR transactivation activity, serum prostate-specific antigen levels, and cell proliferation. NF-kappaB inhibitors decrease AR expression levels, prostate-specific antigen secretion, and proliferation of prostate cancer cells in vitro. Furthermore, inhibitors of NF-kappaB demonstrated anti-tumor activity in androgen deprivation-resistant prostate cancer xenografts. In addition, levels of both NF-kappaB and AR were strongly correlated in human prostate cancer. Our data suggest that NF-kappaB can regulate AR expression in prostate cancer and that NF-kappaB inhibitors may have therapeutic potential.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 36, New York, NY 10065, USA. zhangl2@mskcc.org
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.forename: Saleh
authors.initials: S
authors.lastname: Altuwaijri
authors.forename: Fangming
authors.initials: F
authors.lastname: Deng
authors.forename: Lishi
authors.initials: L
authors.lastname: Chen
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.forename: Umeshkumar K
authors.initials: UK
authors.lastname: Bhanot
authors.forename: Ruslan
authors.initials: R
authors.lastname: Korets
authors.forename: Sven
authors.initials: S
authors.lastname: Wenske
authors.forename: Hans G
authors.initials: HG
authors.lastname: Lilja
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics*; D012717:Sesquiterpenes / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D016328:NF-kappa B; D011944:Receptors, Androgen; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; C002669:parthenolide