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

Cellular proliferation is regulated by cell cycle progression which, in tur n, is controlled by sequential activation of various cyclin-dependent kinas es (CDKs). To explore the mechanism(s) by which long chain polyunsaturated fatty acids (PUFAs) influence the growth of tumor cells, we compared the ef fects of different n-3 and n-6 fatty acids on the activity of CDKs. Docosah exaenoic acid (DHA), a major component of fish oil diets, is able to reduce serum-stimulated cyclin D-1-, E-, and A- associated kinases activity in sy nchronized-HT-29 cells. The inhibitory effect of DHA on cyclin A-associated kinase activity is time-dependent, and is probably modulated by down-regul ation of cyclin A protein expression. In addition, DHA inhibits the phospho rylation of pRb and DNA-binding activity of E2F-1 in response to serum stim ulation, 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 growt h of tumor cells by inhibiting the activation and expression of G(1)-associ ated 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 cel l cycle progression. (C) 2001 Harcourt Publishers Ltd.