2,3,7,8-Tetrachlorodibenzo-p-dioxin blocks androgen-dependent cell proliferation of LNCaP cells through modulation of pRB phosphorylation.
Cell-cycle regulatory events associated with inhibition of androgen-dependent cell proliferation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in the human-derived LNCaP cell line. TCDD blocked the G(1) to S transition of LNCaP cells synchronized in G(0)/G(1) when these cells were induced to reinitiate cell-cycle progression by dihydrotestosterone (DHT). Western blot analyses of these cells revealed altered expression levels of G(1) regulatory proteins, including increases in hypophosphorylated retinoblastoma protein and concomitant decreases in cyclin D1. p21(WAF1/CIP1), which is involved in the assembly of cyclin D1/cyclin-dependent kinase-4 complexes, was increased by DHT or TCDD when each compound was administered singly but was reduced to background levels in cells simultaneously treated with DHT and TCDD. Reporter gene assays revealed the presence of several Ah receptor response-element motifs in the promoter and first intron of the p21(WAF1/CIP1) gene that respond to TCDD-mediated Ah receptor activation independently of p53. Transcription studies showed that activation of aryl hydrocarbon receptor blocks androgen-dependent gene induction in LNCaP cells as well as in African green monkey CV-1 cells. These data point to at least two mechanisms whereby TCDD blocks androgen receptor function: 1) by blocking androgen-induced cell proliferation through modulation of the expression and activities of regulatory proteins controlling cell-cycle progression; and 2) by squelching androgen receptor-mediated gene transcription through receptor cross-talk, possibly involving competition for coregulators or by direct protein interaction.
Barnes-Ellerbe
Sonya
S
Center for Environmental Genetics, Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056, USA.
Knudsen
Karen E
KE
Puga
Alvaro
A
D000728:Androgens / Q000502:physiology; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000728:Androgens; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1