title: Transinactivation of the epidermal growth factor receptor tyrosine kinase and focal adhesion kinase phosphorylation by dietary flavonoids: effect on invasive potential of human carcinoma cells.
abstract: Focal adhesion kinase (FAK), a member of a growing family of structurally distinct protein tyrosine kinases (PTK), has been linked to specific phosphorylation events, and the elevation of FAK activity in human carcinoma cells correlated with increased invasive potential. Transactivation of the epidermal growth factor receptor (EGFR) tyrosine kinase activity is proposed to stimulate cell migration and the subsequent activation of downstream signaling pathways. Quercetin (Qu) and luteolin (Lu), are potent PTK inhibitors as well as putative chemopreventive agents. The present work, we demonstrate that Qu and Lu at concentration of 20 microM transinactivated EGFR tyrosine kinase activity with marked reduction in phosphotyrosyl level of 170, 125, 65, 60 and 42 kDa cellular proteins, and induced apoptosis in MiaPaCa-2 cells. The 125 kDa protein was further identified as a FAK by immunoprecipitation and immunoblotting analyses. Tumor cells treated with Lu or Qu dampened the phosphorylation of FAK. In addition, our data clearly demonstrated that tumor cells responded to Qu and Lu by parallel reductions in the levels of phosphorylated FAK and the secreted matrix metalloproteinase (MMP) that may lead to the suppression of invasive potential and cell migration in vitro. While the molecular mechanism of FAK regulation of MMP secretion in tumor cells remains unclear, our results suggested that blockade of the EGFR-signaling pathway may contributed to the net effect. As suggested in the current study, targeting EGFR and FAK with the objective of modulating their regulatory pathways could offer prospects for the treatment of EGFR-responsive cancers in the future.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Lung-Ta
authors.initials: LT
authors.lastname: Lee
authors.forename: Ying-Tang
authors.initials: YT
authors.lastname: Huang
authors.forename: Jiuan-Jiuan
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Amy Y-L
authors.initials: AY
authors.lastname: Lee
authors.forename: Ferng-Chun
authors.initials: FC
authors.lastname: Ke
authors.forename: Chang-Jen
authors.initials: CJ
authors.lastname: Huang
authors.forename: Chithan
authors.initials: C
authors.lastname: Kandaswami
authors.forename: Ping-Ping H
authors.initials: PP
authors.lastname: Lee
authors.forename: Ming-Ting
authors.initials: MT
authors.lastname: Lee
mesh_terms: D002277:Carcinoma / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D004032:Diet; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D047311:Luteolin; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D013347:Subcellular Fractions; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D005419:Flavonoids; D014443:Tyrosine; D004815:Epidermal Growth Factor; D011794:Quercetin; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020782:Matrix Metalloproteinases; D047311:Luteolin