Ethanol enhances the stimulatory effects of lysophosphatidic acid on DNA synthesis but not cell proliferation in human and mouse fibroblasts

Lysophosphatidic acid (LPA), a constituent of serum, is a positive regulato r of cell growth, while ethanol (EtOH) has been shown to exert both inhibit ory and stimulatory effects on mitogenesis. In this work, we examined possi ble interactions between the effects of EtOH and LPA on DNA synthesis, cell proliferation, activating phosphorylation of p44/p42 mitogen-activated pro tein kinases (MAPK), and p70 S6 kinase (p70 S6K) activity. In fibroblasts d erived from human or mouse embryo or the skin of healthy human subjects, LP A (1-20 mu M) and EtOH (40-80 mM) synergistically stimulated DNA synthesis in a zinc-dependent manner. Nevertheless, EtOH did not modify the stimulato ry effect of LPA on the proliferation of human embryonal fibroblasts. In th e presence of zinc, EtOH did not affect LPA-induced activating phosphorylat ion of p42/p44 MAPKs, although an inhibitor of MAPK kinase inhibited the co mbined effects of LPA and EtOH on DNA synthesis. In contrast, in the presen ce of zinc, EtOH enhanced the stimulatory effect of LPA on p70 S6K activity . The results indicate that in human fibroblasts, in the presence of zinc, EtOH enhances the stimulatory effects of LPA on DNA synthesis, but not on c ell proliferation, by a mechanism probably involving activation of p70 S6K. (C) 2000 Academic Press.