title: Docosahexaenoic acid, a major constituent of fish oil diets, prevents activation of cyclin-dependent kinases and S-phase entry by serum stimulation in HT-29 cells.
abstract: Cellular proliferation is regulated by cell cycle progression which, in turn, is controlled by sequential activation of various cyclin-dependent kinases (CDKs). To explore the mechanism(s) by which long chain polyunsaturated fatty acids (PUFAs) influence the growth of tumor cells, we compared the effects of different n-3 and n-6 fatty acids on the activity of CDKs. Docosahexaenoic acid (DHA), a major component of fish oil diets, is able to reduce serum-stimulated cyclin D1-, E-, and A- associated kinases activity in synchronized-HT-29 cells. The inhibitory effect of DHA on cyclin A-associated kinase activity is time-dependent, and is probably modulated by down-regulation of cyclin A protein expression. In addition, DHA inhibits the phosphorylation of pRb and DNA-binding activity of E2F-1 in response to serum stimulation, and prevents the serum-stimulated entry of S-phase in HT-29 cells. These results indicate that DHA may exert its negative effect on the growth of tumor cells by inhibiting the activation and expression of G1-associated cell cycle regulatory proteins. Since the synthetic antioxidant BHT is able to reverse the inhibition of serum-stimulated activation of cyclin A/CDK by DHA in a dose-dependent manner, endogenous oxidative stress produced by lipid peroxidation in HT-29 cells may be involved in the control of cell cycle progression.
authors.affiliation: Department of Medicine, Section of Endocrinology, Nutrition and Diabetes, Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Chen
authors.forename: N W
authors.initials: NW
authors.lastname: Istfan
mesh_terms: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005395:Fish Oils / Q000008:administration & dosage*; D005434:Flow Cytometry; D005656:Fungal Proteins; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D021122:Protein Subunits; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000187:drug effects*; D012697:Serine Endopeptidases / Q000378:metabolism; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004042:Dietary Fats, Unsaturated; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D005231:Fatty Acids, Unsaturated; D005395:Fish Oils; D005656:Fungal Proteins; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D004281:Docosahexaenoic Acids; D011494:Protein Kinases; C102333:histone H1 kinase; D018844:Cyclin-Dependent Kinases; D012697:Serine Endopeptidases