Role of arachidonic acid metabolism in the mitogenic response of BALB/c 3T3 fibroblasts to epidermal growth factor.

We have investigated the involvement of arachidonic acid release and metabolism in the mitogenic response, i.e., [3H]thymidine incorporation, to epidermal growth factor (EGF) in BALB/c 3T3 cells. EGF induces release of arachidonate and prostaglandin (PG) formation after its addition to BALB/c 3T3 cells at the same concentrations that stimulate mitogenesis. Further, EGF-stimulated mitogenesis is blocked by inhibitors of arachidonate metabolism including indomethacin, eicosatetraynoic acid, and dexamethasone, whereas the addition of major arachidonate products in BALB/c 3T3 cells, PGE2, PGF2 alpha, and their intermediates PGG2 and PGH2, stimulate mitogenesis in synergism with EGF. The addition of PGs to BALB/c 3T3 cells also overcame indomethacin- and eicosatetraynoic acid-inhibited responses to EGF. Indomethacin must be added with EGF in order to block arachidonate metabolism and subsequent mitogenesis. These results suggest that the release of arachidonic acid and its subsequent metabolism is an apparent early requirement for the initiation of cell cycle traversal by EGF.