Regulation of lysophospholipid signaling in development and cancer
Hurst, Jillian Heyward
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Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids that mediate their effects through the activation of G-protein coupled receptors (GPCRs). LPA and S1P mediate a broad range of cellular activities including proliferation, survival, motility, adhesion, cytoskeletal changes, and differentiation. Further, LPA and S1P signaling play a role in multiple physiological and pathophysiological processes. The goal of this research was to define the regulation of LPA and S1P signaling pathways in neural development and ovarian cancer. LPA and S1P are required for proper development of the central nervous system. A stable, adherent human embryonic stem cell-derived neuroepithelial (hES-NEP) cell line has recently been established. We therefore characterized the responses to LPA and S1P in these cells to determine 1) if hES-NEP cells express lysophospholipid receptors and 2) if LPA and S1P mediate cellular responses critical for neural development. Our data demonstrate that hES-NEP cells express functional LPA and S1P receptors, which modulate hES-NEP cell growth and morphology through distinct mechanisms. Further, these data establish hES-NEP cells as a model system for studying the role of lysophospholipids in human neural progenitors. LPA is the predominant growth factor in ovarian cancer, promoting growth, survival, migration, and invasion. The goal of this study was to characterize the signaling pathways regulating LPA signaling in ovarian cancer. Using pharmacological inhibitors we demonstrated that LPA-stimulated cell growth is mediated by distinct sets of receptors and signaling intermediates in two different model ovarian cancer cell lines. We also explored the role of Regulator of G-protein Signaling (RGS) proteins in the regulation of LPA signaling in ovarian cancer cells. RGS proteins are a diverse group of multifunctional proteins which regulate signaling downstream of GPCRs. Our data establish RGS proteins as novel regulators of LPA signaling in ovarian cancer cells and demonstrate that RGS transcripts are differentially expressed in benign and cancerous ovarian tissue.