Cancer cells resort to aerobic glycolysis to meet the increased energy consumption and growth requirement during active proliferation. While it has been observed that the cancer cells preferentially shift to aerobic glycolysis, the extraneous growth factors involved in this process is largely unknown. Since our previous studies have shown that lysophosphatidic acid (LPA) plays a critical role in the pathophysiology of ovarian cancers, we investigated the role of LPA in the metabolic reprogramming of ovarian cancer cells. Our results using XFe96 analyzer indicate that LPA stimulates aerobic glycolysis in multiple ovarian cancer cell lines as well as in patient-derived ovarian cancer cells. Physiological role for LPA in this process is demonstrated by the observation that the inhibitors of LPA-receptors attenuate the glycolytic shift stimulated by the ascitic fluid derived cancer patients. We further demonstrate that the silencing Gαi2, a downstream signaling mediator for LPA, inhibits LPA-stimulated glycolytic shift in ovarian cancer cells. Further analyses indicated that LPA-stimulated metabolic reprogramming involves the generation of reactive oxygen species (ROS). Treatment of cells with N-Acetyl Cysteine (NAC), a ROS-scavenger, inhibited the glycolytic shift stimulated by LPA. In addition, our studies point to a role for LPA-stimulated HIF1α activation in this process. These results indicate that LPA-stimulated metabolic reprogramming in ovarian cancer cells involve ROS-generation via LPA-Gαi2-HIF1α-dependent signaling pathway. Together with the findings that the glycolytic shift is crucially involved in tumor cell survival our studies point to LPA-Gαi2-HIF1α signaling axis as a potential target for therapy in ovarian cancer.

Citation Format: Ji Hee Ha, Rangasudhagar Radhakrishnan, Jeremy D. Ward, Muralidharan Jayaraman, Danny N. Dhanasekaran. LPA stimulates glycolytic shift in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5426. doi:10.1158/1538-7445.AM2017-5426