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

Sujit Nair, Avantika Barve, Tin Oo Khor, Guo Xiang Shen, Wen Lin, Jefferson Y. Chan, Li Cai, Ah Ng Kong

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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 mol/L) and EGCG (20 or 100 mol/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.

Original languageEnglish (US)
Pages (from-to)1223-1240
Number of pages18
JournalActa Pharmacologica Sinica
Volume31
Issue number9
DOIs
StatePublished - Sep 2010

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Keywords

  • AP-1
  • ATF-2
  • EGCG
  • ELK-1
  • Nrf2
  • gene expression profiles
  • prostate cancer
  • sulforaphane

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