LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response.

Abstract

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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 8 Pg. 1923-1934 (04 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29386184 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Lysophospholipids
• RAC1 protein, human
• Reactive Oxygen Species
• Receptors, G-Protein-Coupled
• NADPH Oxidases
• Hexokinase
• rac1 GTP-Binding Protein
• lysophosphatidic acid

Topics

• Animals
• Cell Hypoxia
• Cell Line, Tumor
• Female
• Glycolysis
• Heterografts
• Hexokinase (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Lysophospholipids (metabolism)
• Mice
• Mice, Nude
• NADPH Oxidases (metabolism)
• Ovarian Neoplasms (metabolism, pathology)
• Reactive Oxygen Species (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• rac1 GTP-Binding Protein (metabolism)