Evaluating the Role of the Na+‐H+ Exchanger Isoform 1 (NHE1) in Lysophosphatidic Acid and Urokinase‐type Plasminogen Activator Stimulation of Ovarian Cancer Cells

Abstract

Lysophosphatidic Acid (LPA) is a bioactive lipid which stimulates an increase in cell proliferation and migration in a range of normal and cancer lines in part through the activation of both the RhoA/Rock and Ras/ErK signaling pathways. Plasma levels of LPA are elevated in ovarian cancer patients even in the early stages of the disease where it is believed to participate in pathogenesis. In patients with more advanced stages of ovarian cancer, the higher the levels of LPA found in the blood and ascites is a negative prognostic indicator. In ovarian cancer, LPA enhances cell proliferation and promotes cell survival by preventing apoptosis and anoikis. LPA also decreases the sensitivity of the ovarian cancer cells to cisplatin and other chemotherapy drugs. While LPA signaling can directly enhance ovarian cancer progression, it can also act by stimulating the production and release of urokinase‐type plasminogen activator (uPA). uPA is a serine protease that binds to a plasma membrane receptor stimulating activation of both the RhoA/Rock and Ras/ErK signaling pathways. Studies in non‐small cell lung cancer cells have shown that LPA and uPA activate the Na+‐H+ Exchanger Isoform 1 (NHE1) leading to an increase in cell proliferation and migration. NHE1 is an 815 amino acid transmembrane protein that exchanges 1 extracellular Na+ for 1 intracellular H+ leading to the pH inversion common to cancer cells in a developing tumor. Activation of NHE1 is one of the initial steps in the development of the transformed phenotype of cancer cells. NHE1 can be phosphorylated and activated by Rock and kinases in the Ras/Erk signaling pathway. Recently, increases in NHE1 expression was demonstrated to play an important role in cancer progression in ovarian cancer patients. In this project, we specifically explore the relationship between LPA and uPA signaling to NHE1 in the regulation of cell proliferation, stress fiber formation, and cell migration in three ovarian cancer cell lines, CAOV‐3, SKOV‐3, and OVCAR‐3.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.