The molecular pharmacology of lysophosphatidic acid and sphingosine 1-phosphate receptors in ovarian cancer and human neural progenitor cells
Callihan, Charles Phillip
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GPCRs are transmembrane proteins that mediate cellular responses to a wide-range of molecules by transmitting signals through intracellular heterotrimeric G-proteins. Through these G-proteins, GPCRs regulate the development and physiology of numerous systems in the human body, and are implicated in many human diseases. The lysophospholipids lysophoshphatidic acid (LPA) and sphingosine 1-phosphate (S1P) activate a family of GPCRs to regulate cell growth and differentiation. This dissertation will focus on lysophospholipid signaling in ovarian cancer, stem cell pluripotency, and neural progenitor cells. Ligand binding to GPCRs induces the exchange of GDP for GTP on the Gα-subunit of the heterotrimeric G-protein, resulting in the activation of downstream signaling pathways. G-protein signaling is terminated through the action of Regulators of G-Protein Signaling (RGS) proteins. Numerous members of the RGS protein family have been implicated in various types of cancer. Our lab has shown that endogenous RGS proteins regulate LPA receptor signaling in ovarian cancer cells, and a number of RGS proteins are downregulated in chemo-resistant ovarian cancer. The studies described herein test the ability of specific RGS proteins to regulate cell survival signaling in ovarian cancer cells. Our results show that RGS10 inhibits AKT survival signaling pathways downstream of LPA. LPA and S1P are also important regulators of neural tube closure and neuronal differentiation, but the molecular details of this regulation remain undefined. Using human embryonic stem cell derived neuroepithelial progenitor (hES-NEP) cells, we have defined general mechanisms of LPA and S1P signaling in neural progenitors. Our studies show that exposure to the mycotoxin FB1 results in preferential increases in dihydrosphingosine over sphingosine, and that their receptor active 1-phosphate metabolites, dhS1P and S1P, display distinct pharmacology in hES-NEP cells. Finally, we found that LPA and S1P suppress neuronal differentiation of hES-NEP cells and enhance survival. Our results indicate that this suppression is due to LPA/S1P activation of Erk, and inhibition of AKT signaling pathways, with distinct roles for distinct receptor subtypes.