Abstract 1141: LPA stimulates glycolytic shift of ovarian cancer cells via gip2 oncogenes

Ovarian cancer patients show increased levels of lysophosphatidic acid (LPA) in their serum and ascitic fluid. Our previous studies have established a critical role for LPA in inducing proliferation as well as migration of ovarian cancer cells. In the present study, we focused on identifying novel therapeutic targets in the oncogenic signaling pathway regulated by LPA. Using a commercial pathway reporter array of 45 transcription factors, we found that hypoxia-induced factor-1 alpha (HIF-1 alpha) was the most activated transcription factor induced by LPA. Both stable as well as transient silencing of Galphai2, a downstream signaling mediator for LPA, abrogates LPA induced increase in HIF-1 alpha expression. In addition, our results indicate that LPA stimulated an increase in the expression of Hexokinase-2 (HK2) and Glucose transporter 1 (GLUT1), which are targets of HIF-1 alpha, are also mediated via Galphai2 signaling pathway. To determine the outcome LPA induced increase in HK2 and GLUT1 on glycolytic rates, we measured the extracellular acidification rate (ECAR) in ovarian cancer cells following treatment with LPA, using an XFe analyzer. In both SKOV3-ip and OVCA429 cells, LPA increased ECAR in a dose-dependent manner. Silencing Galphai2 as well as HIF-1 alpha in ovarian cancer cells reduced ECAR indicative of reduced glycolytic rate. The current study, points to the identification of LPA(R)-Galphai2-HIF-1 alpha-GLUT1 signaling axis as potential metabolism-targets in ovarian cancer treatment. Citation Format: Ji Hee Ha, Rangasudhagar Radhakrishnan, Danny Dhanasekaran. LPA stimulates glycolytic shift of ovarian cancer cells via gip2 oncogenes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1141. doi:10.1158/1538-7445.AM2015-1141