The flavonols quercetin, kaempferol, and myricetin inhibit hepatocyte growth factor-induced medulloblastoma cell migration.
Medulloblastoma, the most common malignant brain tumor in children, is a highly metastatic disease, with up to 30% of children having evidence of disseminated disease at presentation. Recently, the hepatocyte growth factor (HGF) and its receptor, the tyrosine kinase Met, have emerged as key components of human medulloblastoma growth and metastasis, suggesting that inhibition of this pathway may represent an attractive target for the prevention and treatment of this disease. Using immunoblotting procedures, we observed that the dietary-derived flavonols quercetin, kaempferol, and myricetin inhibited HGF/Met signaling in a medulloblastoma cell line (DAOY), preventing the formation of actin-rich membrane ruffles and resulting in the inhibition of Met-induced cell migration in Boyden chambers. Furthermore, quercetin and kaempferol also strongly diminished HGF-mediated Akt activation. Interestingly, the inhibitory effects of quercetin on the tyrosine kinase receptor Met [half-maximal inhibitory effect (IC(50)) of 12 micromol/L] or on the Met-induced activation of Akt (IC(50) of 2.5 micromol/L) occurred at concentrations achievable through dietary approaches. These results highlight quercetin, kaempferol, and myricetin as dietary-derived inhibitors of Met activity and suggest that this inhibitory effect may contribute to the chemopreventive properties of these molecules.
Labbé
David
D
Laboratoire de Médecine Moléculaire, Département de Chimie-Biochimie, Université du Québec à Montréal, C.P. 8888, Succursale Centre-ville, Montréal, Québec, Canada, H3C 3P8.
Provençal
Mathieu
M
Lamy
Sylvie
S
Boivin
Dominique
D
Gingras
Denis
D
Béliveau
Richard
R
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D044949:Kaempferols / Q000494:pharmacology*; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D011794:Quercetin / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D005419:Flavonoids; D007211:Indoles; D044949:Kaempferols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D013449:Sulfonamides; D017228:Hepatocyte Growth Factor; C006552:kaempferol; C040015:myricetin; D011794:Quercetin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt