LYSOPHOSPHATIDIC ACID POSSESSES DUAL-ACTION IN CELL-PROLIFERATION

Lysophosphatidic acid (LPA) induces mitogenic responses in cultured fi broblasts through a pertussis toxin-sensitive signaling pathway. In co ntrast, we have shown that LPA inhibits the proliferation of Sp2/0-Ag1 4 myeloma cells. To resolve this apparent controversy, LPA-elicited re sponses in cell proliferation and the underlying second messenger mech anisms were compared in Sp2/0-Ag14 myeloma and NIH 3T3 fibroblast cell s. The antimitogenic response was not elicited by micromolar concentra tions of phosphatidic acid, phosphatidylglycerol, or diacylglycerol. I n NIH 3T3 and Sp2 cells, LPA elicited an increase in inositol trisphos phate and a subsequent transient increase in free cytoplasmic Ca2+. Un like the mitogenic response in NIH 3T3 cells, the antimitogenic effect was not affected by pertussis toxin; on the contrary, it was accompan ied by an increase in cAMP. In Sp2 cells, cAMP analogs, forskolin, and isobutylmethylxanthine inhibited cell proliferation and enhanced LPA action in an additive manner, suggesting that an LPA-elicited increase in cAMP-mediated signaling was responsible for the antimitogenic resp onse. In addition to the mitogenic response in fibroblasts and the ant imitogenic response in tumor cell lines, there are some cell types (Ju rkat T-cell lymphoma and primary astrocytes) in which LPA is ineffecti ve in altering cell proliferation. The cell-type-specific dual action of LPA suggests that this endogenous lipid mediator when released from activated cells might play an important role as a regulator, rather t han a ubiquitous inducer, of cell proliferation.