期刊
ACTA PHARMACOLOGICA SINICA
卷 31, 期 9, 页码 1223-1240出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/aps.2010.147
关键词
prostate cancer; sulforaphane; EGCG; Nrf2; AP-1; ATF-2; ELK-1; gene expression profiles
资金
- National Institutes of Health (NIH) [RO1-CA118947, RO1-CA094828, R21-CA133675]
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 mu mol/L) and EGCG (20 or 100 mmol/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.
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