Inhibition of LPA signaling pathways by RGS protein overexpression in ovarian cancer cells
Turner, Kathryn Lisa
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Lysophosphatidic acid (LPA) is a signaling molecule that induces survival, metastasis, migration, and proliferation in ovarian cancer cells by binding to G-protein coupled receptors (GPCRs), which in turn activate G-proteins. Regulator of G-Protein Signaling (RGS) proteins deactivate these G-proteins, and therefore stop the LPA signal. RGS proteins are a likely therapeutic target for the cancer causing activities of LPA because there are multiple forms that bind specifically to different G-proteins, therefore potentially regulating specific signals and outcomes. Previous data suggest that RGS proteins play a role in regulating the LPA signal in ovarian cancer cells. By comparing the effects of LPA in RGS sensitive and insensitive cells, we observed differences in cell growth, cell migration, and the production of the second messengers cyclic adenosine monophosphate (cAMP) and inositol phosphate (IP). My current project focuses on overexpressing two distinct RGS proteins and determining their effects on LPA stimulated outcomes of cAMP and cellular migration in SKOV-3 ovarian cancer cells. LPA causes a decrease in the second messenger cAMP, and we have found that overexpression of RGS2 and RGS19 blocks this LPA stimulated inhibition of adenylyl cyclase. Additionally, LPA causes an increase in cellular migration, which is also inhibited by RGS2 and RGS19. Further study will confirm these results by lowering expression of endogenous RGS2 and RGS19 in ovarian cancer cells using siRNA.