title: The SIRT1/HIF2α axis drives reductive glutamine metabolism under chronic acidosis and alters tumor response to therapy.
abstract: Extracellular tumor acidosis largely results from an exacerbated glycolytic flux in cancer and cancer-associated cells. Conversely, little is known about how tumor cells adapt their metabolism to acidosis. Here, we demonstrate that long-term exposure of cancer cells to acidic pH leads to a metabolic reprogramming toward glutamine metabolism. This switch is triggered by the need to reduce the production of protons from glycolysis and further maintained by the NAD(+)-dependent increase in SIRT1 deacetylase activity to ensure intracellular pH homeostasis. A consecutive increase in HIF2α activity promotes the expression of various transporters and enzymes supporting the reductive and oxidative glutamine metabolism, whereas a reduction in functional HIF1α expression consolidates the inhibition of glycolysis. Finally, in vitro and in vivo experiments document that acidosis accounts for a net increase in tumor sensitivity to inhibitors of SIRT1 and glutaminase GLS1. These findings highlight the influence that tumor acidosis and metabolism exert on each other.
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Cyril
authors.initials: C
authors.lastname: Corbet
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nihed
authors.initials: N
authors.lastname: Draoui
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Florence
authors.initials: F
authors.lastname: Polet
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Adan
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Molecules, Solids and Reactivity (MOST), Institute of Condensed Matter and Nanosciences (IMCN), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Drozak
authors.affiliation: Molecules, Solids and Reactivity (MOST), Institute of Condensed Matter and Nanosciences (IMCN), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Riant
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. olivier.feron@uclouvain.be.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002908:Chronic Disease; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D056564:Sirtuin 1 / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005947:Glucose; D005973:Glutamine; D056564:Sirtuin 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C447939:SIRT1 protein, human