G-protein coupled receptor mediated signaling pathways in chemoresistant melanoma and ovarian cancer
Altman, Molly Koertel
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Cellular signaling pathways are involved in numerous physiological processes such as reproduction, growth, and the development of cancer and chemoresistance. G-protein coupled receptors (GPCRs) are master regulators of many signaling pathways as they are expressed in numerous tissues types throughout the body. GPCRs are being investigated in cancer development particularly through their roles in angiogenesis, metastasis, and inflammation-associated cancer. Growth factors that bind and activate GPCRs to mediate signaling pathways involved in growth and survival include lysophosphatidic acid (LPA). In our studies, both in vitro and in vivo methods were used to test the importance of several signaling pathways in chemoresistant cancer cell survival and tumor biology. In our studies, we found that specific Regulators of G-protein signaling (RGS) proteins are involved in modulating growth and survival pathways in ovarian cancer. Specifically, we showed that silencing of RGS10 and RGS17 proteins increases viability of ovarian cancer cells, and we further examined the role of modulating RGS10 expression on cell differentiation, proliferation, and survival pathways. We also showed that the inhibition of autotaxin the enzyme that produces LPA is a potential therapeutic target for melanoma and how LPA mediated receptor pathways can be manipulated to overcome chemoresistance in cancer. Our most valuable observation was that our novel compounds were able to reduce tumor progression in vivo in a primary xenograft model of melanoma in correlation with a reduction in markers of angiogenesis. Our data serves to help better understand signaling pathways involved in the development of chemoresistance.