American Association for Cancer Research
00085472can171624-sup-184143_2_supp_4526834_p32rzt.pdf (124.74 kB)

Figure S6 from LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response

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journal contribution
posted on 2023-03-31, 01:40 authored by Ji Hee Ha, Rangasudhagar Radhakrishnan, Muralidharan Jayaraman, Mingda Yan, Jeremy D. Ward, Kar-Ming Fung, Katherine Moxley, Anil K. Sood, Ciro Isidoro, Priyabrata Mukherjee, Yong Sang Song, Danny N. Dhanasekaran

LPA-stimulated HIF1α is an early response


National Institutes of Health

Priority Research Centers Program

National Research Foundation of Korea

Stephenson Cancer Center-MD Anderson Collaborative Research initiative



Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase and generation of reactive oxygen species, resulting in activation of HIF1α. HIF1α in turn induced expression of glucose transporter-1 and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate, attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer.Significance: These findings establish LPA as a potential therapeutic target in ovarian cancer, revealing its role in the activation of HIF1α-mediated metabolic reprogramming in this disease. Cancer Res; 78(8); 1923–34. ©2018 AACR.