Differential Effects of N-6 and N-3 Polyunsaturated Fatty Acids on Cell Growth and Early Gene Expression in Swiss 3T3 Fibroblasts

Dietary n-3 polyunsaturated fatty acids (PUFAs) have been found to reduce accelerated cell growth. To study the underlying molecular mechanisms, we evaluated the effects of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with the n-6 PUFA arachidonic acid (AA) on cell growth and early gene mRNA accumulation in Swiss 3T3 fibroblasts. AA significantly increased cell numbers and incorporation of [3H]-thymidine compared with cells treated with EPA and DHA, which did not stimulate cell growth. In contrast to AA and parallel to its effect on cell growth, EPA and DHA did not lead to a pronounced increase in Egr-1 and c-fosmRNA levels. When they were incubated together with AA, both DHA and EPA reduced AA-induced Egr-1 and c-fosmRNA accumulation and incorporation of [3H]-thymidine. We have recently shown that AA strongly increases Egr-1 and c-fosmRNA accumulation 3T3 fibroblasts through its metabolism to prostaglandin E2 (PGE2) and its subsequent activation of protein kinase C (Danesch et al., 1994, J. Biol. Chem., 269:27258-27263). Consistent with the notion that increased PGE2 formation is required for the AA-induced early gene mRNA accumulation, EPA and DHA reduced PGE2 formation from exogenous [14C]-AA by more than 60%, but they did not decrease mRNA levels following stimulation with PGE2. We suggest that, in 3T3 fibroblasts, EPA and DHA antagonize AA-induced early gene mRNA accumulation and cell growth by reducing PGE2 formation.