BACKGROUND/AIMS: Lysophosphatidic acid (LPA) is an autocrine growth signal critical to the initiation and progression of ovarian cancer. In the current study, we investigated the receptors and signaling cascades responsible for mediating LPA-stimulated cell growth in SKOV-3 and Caov-3 ovarian cancer cell lines. METHODS: Pharmacological inhibitors of distinct LPA and epidermal growth factor receptors, G proteins and kinases were tested for their effect on LPA-stimulated cell growth, MAP kinase activation and Akt activation in SKOV-3 and Caov-3 cells. RESULTS: Distinct agonist pharmacological profiles were observed. Saturated and unsaturated LPA species were equally potent in Caov-3 cells, while saturated LPA was less potent than unsaturated LPA in SKOV-3 cells. Further, the LPA1/LPA3 receptor antagonist Ki16425 was more potent in SKOV-3 cells. The effect of LPA on cell growth in both cell lines was dependent on phosphatidylinositol-3 kinases and MAP kinases. However, LPA-stimulated SKOV-3 cell growth required Gi G proteins, while Caov-3 cell growth was dependent on the Rho effector p160 Rho kinase. Finally, we demonstrated that regulator of G protein signaling proteins significantly regulated Gi-dependent LPA-stimulated cell growth in SKOV-3 cells. CONCLUSIONS: LPA-stimulated cell growth is mediated by distinct but overlapping receptors and signaling pathways in these two model ovarian cancer cell lines.