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. 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. .

Crucial role of the pentose phosphate pathway in malignant tumors (Review)

“…NSD2-driven tamoxifen-resistant cancers exhibit an enhanced PPP activity, elevated NADPH production and reduced ROS levels. For example, treatment of ovarian cancer xenografted mice with the HK2 inhibitor 3-bromopyruvate attenuates tumor growth and confers a survival advantage (53).…”

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

“…Ha et al found that the LPA-LPAR-Gαi2 axis can induce pseudo hypoxic response through the Rac-NOXROS-HIF1α pathway, which ultimately leaded to metabolic reprogramming of ovarian cancer cells. This conclusion was verified by establishing two independent mouse models of ovarian cancer cell line xenograft (CDX) [58]. PI3K/Akt pathway is critical in the process of ovarian cancer.…”

Activation of macrophages by lysophosphatidic acid through the lysophosphatidic acid receptor 1 as a novel mechanism in multiple sclerosis pathogenesis

“…In this case, the modular expression of different LPA receptors after differential activation hints a complex role of LPA signaling in the homeostasis of macrophages during the disease and suggests that modulating the expression or saturating the activation of one or the other one could be a mechanism of trans-differentiation of human macrophages. Although this aspect requires further study, the fact that LPA1 is related to glycolysis (7,16,33) (main source of energy for pro-inflammatory polarized macrophages) and PPARƔ induces oxidative phosphorylation (35), and that these two metabolic processes are central in pro-and anti-inflammatory macrophage activation respectively (13), suggests that the modulation of these LPA receptors could have major implications in the macrophage physiology and activation.…”