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Title: Regulation of Nrf2- and AP-1-mediated gene expression by epigallocatechin-3-gallate and sulforaphane in prostate of Nrf2-knockout or C57BL/6J mice and PC-3 AP-1 human prostate cancer cells.

Authors: Nair, Sujit; Barve, Avantika; Khor, Tin-Oo; Shen, Guo-xiang; Lin, Wen; Chan, Jefferson Y; Cai, Li; Kong, Ah-Ng

Published In Acta Pharmacol Sin, (2010 Sep)

Abstract: AIM: To examine the regulatory crosstalk between the transcription factors Nrf2 and AP-1 in prostate cancer (PCa) by dietary cancer chemopreventive compounds (-)epigallocatechin-3-gallate (EGCG) from green tea and sulforaphane (SFN) from cruciferous vegetables. METHODS: We performed (i) in vitro studies including luciferase reporter gene assays, MTS cell viability assays, and quantitative real-time PCR (qRT-PCR) in PC-3 AP-1 human PCa cells, (ii) in vivo temporal (3 h and 12 h) microarray studies in the prostate of Nrf2-deficient mice that was validated by qRT-PCR, and (iii) in silico bioinformatic analyses to delineate conserved Transcription Factor Binding Sites (TFBS) in the promoter regions of Nrf2 and AP-1, as well as coregulated genes including ATF-2 and ELK-1. RESULTS: Our study shows that AP-1 activation was attenuated by the combinations of SFN (25 micromol/L) and EGCG (20 or 100 micromol/L) in PC-3 cells. Several key Nrf2-dependent genes were down-regulated (3-fold to 35-fold) after in vivo administration of the combination of EGCG (100 mg/kg) and SFN (45 mg/kg). Conserved TFBS signatures were identified in the promoter regions of Nrf2, AP-1, ATF2, and ELK-1 suggesting a potential regulatory mechanism of crosstalk between them. CONCLUSION: Taken together, our present study of transcriptome profiling the gene expression changes induced by dietary phytochemicals SFN and EGCG in Nrf2-deficient mice and in PC-3 cells in vitro demonstrates that the effects of SFN+EGCG could be mediated via concerted modulation of Nrf2 and AP-1 pathways in the prostate.

PubMed ID: 20729872 Exiting the NIEHS site

MeSH Terms: Animals; Anticarcinogenic Agents/pharmacology*; Antineoplastic Combined Chemotherapy Protocols; Binding Sites; Catechin/analogs & derivatives*; Catechin/pharmacology; Cell Line, Tumor; Cell Survival/drug effects; Gene Expression Regulation, Neoplastic/drug effects*; Humans; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2/genetics*; NF-E2-Related Factor 2/metabolism; Promoter Regions, Genetic; Prostatic Neoplasms/drug therapy*; Prostatic Neoplasms/genetics; Thiocyanates/pharmacology*; Transcription Factor AP-1/genetics*; Transcription Factor AP-1/metabolism

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