ICI 182,780-regulated gene expression in DU145 prostate cancer cells is mediated by estrogen receptor-beta/NFkappaB crosstalk.
Estrogen receptor (ER)-beta is the predominant ER subtype in prostate cancer (PCa). We previously demonstrated that ICI 182,780 (ICI), but not estrogens, exerted dose-dependent growth inhibition on DU145 PCa cells by an ER-beta-mediated pathway. Transcriptional profiling detected a greater than three-fold upregulation of seven genes after a 12-hour exposure to 1 microM ICI. Semiquantitative reverse transcriptase polymerase chain reaction confirmed the upregulation of four genes by ICI: interleukin-12alpha chain, interleukin-8, embryonic growth/differentiation factor, and RYK tyrosine kinase. Treatment with an ER-beta antisense oligonucleotide reduced cellular ER-beta mRNA and induced loss of expression of these genes. Sequence analysis revealed the presence of consensus NFkappaB sites, but not estrogen-responsive elements, in promoters of all four genes. Reporter assay and chromatin immunoprecipitation experiments demonstrated that ICI-induced gene expression could be mediated by crosstalk between ER-beta and the NFkappaB signaling pathway, denoting a novel mechanism of ER-beta-mediated ICI action. Therefore, combined therapies targeting ER-beta and NFkappaB signaling may be synergistic as treatment for PCa.
Leung
Yuet-Kin
YK
Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Gao
Ying
Y
Lau
Kin-Mang
KM
Zhang
Xiang
X
Ho
Shuk-Mei
SM
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000378:metabolism*; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D055452:Growth Differentiation Factor 1; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis
D018931:Antineoplastic Agents, Hormonal; D047629:Estrogen Receptor beta; C525977:GDF1 protein, human; D055452:Growth Differentiation Factor 1; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D018664:Interleukin-12; D000077267:Fulvestrant; D004958:Estradiol; C080836:RYK protein, human; D020794:Receptor Protein-Tyrosine Kinases