| Lysophospholipids0, such as lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC) are present in serum and plasma in normal and disease states. LPA, S1P, and SPC cause a variety of effects on cells acting through G protein-coupled receptors (GPCRs) on the cell surface. Using GeneChip analyses, we have identified several genes that are regulated by LPA, S1P, and SPC in ovarian cancer cells. We have furthered our studies to specifically focus on LPA- and S1P-induced regulation of the Akt2 gene, as well as the Akt protein, a proto-oncogene involved in many different kinds of cancer, including ovarian cancer.; LPA and S1P induce activation of Akt in a manner dependent on the G i protein, phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase kinase (MEK), and p38 MAP kinase, and MEK is likely to be upstream of p38 in this pathway. The requirement for both MEK and p38 is cell type- and stimulus-specific. T308 phosphorylation stimulated by LPA/S1P requires MEK, but not p38 activation. MEK and p38 activation were sufficient for Akt S473, but not T308, phosphorylation. LPA/S1P-induced Akt activation may be involved in cell survival, since LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/MEK/p38-dependent manner.; S1P-, but not LPA-, induced activation of Akt requires the kinase activity of the platelet-derived growth factor receptor (PDGFR) in a panel of cell lines. We show for the first time that S1P can induce tyrosine phosphorylation of PDGFR, which occurs in a Gi-dependent manner. S1P receptor expression suggests that S1P3 is involved in PDGFR-mediated Akt activation. This is supported by CHO cells overexpressing S1P3, which require PDGFR for Akt activation. S1P- and PDGF-induced Akt activation in S1P 3-null mouse embryonic fibroblasts (MEFs) are almost completely abolished and dramatically decreased, respectively, compared to wild-type MEF cells. In CHO cells overexpressing S1P3, PDGFR and S1P3 co-immunoprecipitate together, indicating that they form a complex to produce more efficient stimulation of the Akt signaling pathway. |
