Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1.
We have investigated the effects of a series of flavonoids on cell proliferation and cell cycle distribution in human melanoma cells OCM-1. Among the compounds that potently inhibited OCM-1 cell proliferation, we show that the presence of a hydroxyl group at the 3'-position of the ring B in quercetin and luteolin, correlated to a G1 cell cycle arrest while its absence in kaempferol and apigenin correlated to a G2 block. Genistein with a hydroxyl at 5-position of the ring A arrested cells in G2 while daidzein which lacks it, induced an accumulation of cells in G1. We demonstrate that flavonoids, which induced a cell cycle block in G1, inhibited the activity of CDK2 by 40-60%. By contrast, those which caused an accumulation of cells in G2/M were without effect. On the other hand, while quercetin, daidzein and luteolin did not alter the activity of CDK1, kaempferol, apigenin and genistein inhibited this kinase by 50-70%. We demonstrate that the up-regulation of the CDK inhibitors p27(KIP1) and p21(CIP1) is likely responsible for the inhibition of CDK2 while inhibition of CDK1 was rather due to the phosphorylation of the kinase on Tyr15 residue.
Casagrande
F
F
Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, UMR 5088 CNRS, Université Paul Sabatier, 118 route de Narbonne, F-31062 cedex, Toulouse, France
Darbon
J M
JM
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000187:drug effects
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D005419:Flavonoids; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases