Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer

Abstract

Mitochondria are the sites of pyruvate oxidation, citric acid cycle, oxidative phosphorylation, ketogenesis, and fatty acid oxidation. Attenuation of mitochondrial function is one of the most significant changes that occurs in tumor cells, directly linked to oncogenesis, angiogenesis, Warburg effect, and epigenetics. In particular, three mitochondrial enzymes are inactivated in cancer: pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and 3-hydroxy-3-methylglutaryl CoA synthase-2 (HMGCS2). These enzymes are subject to regulation via acetylation/deacetylation. SIRT3, the predominant mitochondrial deacetylase, directly targets these enzymes for deacetylation and maintains their optimal catalytic activity. SIRT3 is a tumor suppressor, and deacetylation of these enzymes contributes to its biological function. PDH catalyzes the oxidative decarboxylation of pyruvate into acetyl CoA, SDH oxidizes succinate into fumarate, and HMGCS2 controls the synthesis of the ketone body β-hydroxybutyrate. As the activities of these enzymes are decreased in cancer, tumor cells accumulate lactate and succinate but produce less amounts of β-hydroxybutyrate. Apart from their role in cellular energetics, these metabolites function as signaling molecules via specific cell-surface G-protein-coupled receptors. Lactate signals via GPR81, succinate via GPR91, and β-hydroxybutyrate via GPR109A. In addition, lactate activates hypoxia-inducible factor HIF1α and succinate promotes DNA methylation. GPR81 and GPR91 are tumor promoters, and increased production of lactate and succinate as their agonists drives tumorigenesis by enhancing signaling via these two receptors. In contrast, GPR109A is a tumor suppressor, and decreased synthesis of β-hydroxybutyrate as its agonist suppresses signaling via this receptor, thus attenuating the tumor-suppressing function of GPR109A. In parallel with the opposing changes in lactate/succinate and β-hydroxybutyrate levels, tumor cells upregulate GPR81 and GPR91 but downregulate GPR109A. As such, these three metabolite receptors play a critical role in cancer and represent a new class of drug targets with selective antagonists of GPR81 and GPR91 for cancer treatment and agonists of GPR109A for cancer prevention.

The In Vitro Anti-Tumor Activity of Phycocyanin against Non-Small Cell Lung Cancer Cells

“…Cell cycle regulation plays an important role in cell proliferation, differentiation, and apoptosis. It has been reported that cell cycle regulation dysfunction is closely related to the development of tumors [ 38 ]. Peyressatre et al found that the deregulated activity of cyclin-dependent kinases (CDKs) contributes to altered cellular proliferation in a wide variety of human cancers [ 39 ].…”

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…GPR81 activation occurs at a lactate concentration of 0.2-1.0 mM (119), followed by cyclic AMP downregulation and inhibition of protein kinase A (PKA)-mediated signaling (120). In the physiological context, lactate binds to GPR81, which inhibits lipolysis in fat cells (121). In the cancer context, modulation of lactate-sensing proteins, such as MCTs, ultimately leads to tumor proliferation and dissemination (122), escape from the immune system (123) and therapy resistance (124).…”

Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness

“…Importantly, besides the canonical role as nutrient, lactate has been shown to act as a hormone, as it is able to activate signaling pathways downstream the hydroxycarboxylic acid receptor 1, formerly known as G protein-coupled receptor 81 (GPR81). This receptor, sensitive to low concentrations of lactate (1-5 mM), is coupled to G i/q , and activation of the receptor results in decreased cellular levels of cAMP and increased cellular levels of Ca 2+ , leading a fascinating hypothesis of an autocrine and paracrine role of lactate in cancerous and stromal cell types via surface receptor (59,60). Very recently, another non-nutritional role of lactate has been reported by Zhang et al (61).…”