title: Flavonoid phytochemicals regulate activator protein-1 signal transduction pathways in endometrial and kidney stable cell lines.
abstract: Phytochemicals bind to and regulate the human estrogen receptors (ERalpha and ERbeta), mimicking actions of the endogenous estrogen, 17beta-estradiol, and known antiestrogens such as ICI 182,780. Recently, however, some of these estrogenic phytochemicals have been shown to affect other signal transduction pathways, such as receptor tyrosine kinases and mitogen-activated protein kinases (MAPK). Previously, we found that certain phytochemicals, such as flavone, apigenin, kaempferide and chalcone, have potent antiestrogenic activity. However, the antiestrogenicity of these compounds does not correlate with their ER binding capacity, suggesting alternative signaling as a mechanism for their antagonistic effects. In this study, we examined the effects of these compounds on the transcription factor activator protein-1 (AP-1). Using AP-1-luciferase stable human endometrial adenocarcinoma Ishikawa and human embryonic kidney (HEK) 293 cells, chalcone, flavone and apigenin all stimulated AP-1 activity. Additionally, we determined the effects of the phytochemicals on transcription factors that are downstream targets of various MAPK pathways. To test this, we used HEK 293 cells stably cointegrated with GAL4 transcriptional activation systems of Elk-1, c-Jun or C/EBP homologous protein (CHOP). Chalcone was the only phytochemical that activated all three transcription factors [Elk-1, 2.7-fold (P < 0.001); c-Jun, 2.7-fold (P = 0.025); CHOP, 3.0-fold (P = 0.002)], whereas apigenin stimulated CHOP (3.9-fold; P < 0.001), but inhibited phorbol myristoyl acetate-induced c-Jun activity (71%;P = 0.006). This work suggests that phytochemicals affect multiple signaling pathways that converge at the level of transcriptional regulation. The ability of flavonoids to regulate MAPK-responsive pathways in a selective manner indicates a mechanism by which phytochemicals may influence human health and disease.
authors.affiliation: Environmental Endocrinology Laboratory, Center for Bioenvironmental Research, Tulane and Xavier Universities, New Orleans, LA 70112, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
authors.forename: Bich N
authors.initials: BN
authors.lastname: Duong
authors.forename: Lilia I
authors.initials: LI
authors.lastname: Melnik
authors.forename: Lawanda S
authors.initials: LS
authors.lastname: Schief
authors.forename: Bridgette M
authors.initials: BM
authors.lastname: Collins-Burow
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Pace
authors.forename: John A
authors.initials: JA
authors.lastname: McLachlan
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins; D004717:Endometrium / Q000166:cytology / Q000502:physiology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000502:physiology; D050807:ets-Domain Protein Elk-1
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D005419:Flavonoids; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D051742:Transcription Factor CHOP