Flavonoid Phytochemicals Regulate Activator Protein-1 Signal Transduction Pathways in Endometrial and Kidney Stable Cell Lines

EPA Grant Number: U916008
Title: Flavonoid Phytochemicals Regulate Activator Protein-1 Signal Transduction Pathways in Endometrial and Kidney Stable Cell Lines
Investigators: Schief, Lawanda S.
Institution: Tulane University of Louisiana
EPA Project Officer: Lee, Sonja
Project Period: August 1, 2001 through August 1, 2004
Project Amount: $71,660
RFA: STAR Graduate Fellowships (2001) RFA Text |  Recipients Lists
Research Category: Fellowship - Toxicology , Academic Fellowships , Health Effects


The objective of this research project is to examine the effects of certain phytochemicals on the transcription factor activator protein-1 (AP-1).


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. Using AP-1-luciferase stable human endometrial adenocarcinoma Ishikawa and human embryonic kidney (HEK) 293 cells, chalcone, flavone, and apigenin 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 percent; P = 0.006). This research project 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.

Supplemental Keywords:

fellowship, flavonoid phytochemicals, estrogen receptor, ER, mitogen-activated protein kinase, activator protein-1, AP-1.

Progress and Final Reports:

  • 2002
  • 2003
  • Final