title: Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors.
abstract: The monocarboxylate transporter (MCT) family member MCT1 can transport lactate into and out of tumor cells. Whereas most oxidative cancer cells import lactate through MCT1 to fuel mitochondrial respiration, the role of MCT1 in glycolysis-derived lactate efflux remains less clear. In this study, we identified a direct link between p53 function and MCT1 expression. Under hypoxic conditions, p53 loss promoted MCT1 expression and lactate export produced by elevated glycolytic flux, both in vitro and in vivo. p53 interacted directly with the MCT1 gene promoter and altered MCT1 mRNA stabilization. In hypoxic p53(-/-) tumor cells, NF-κB further supported expression of MCT1 to elevate its levels. Following glucose deprivation, upregulated MCT1 in p53(-/-) cells promoted lactate import and favored cell proliferation by fuelling mitochondrial respiration. We also found that MCT1 expression was increased in human breast tumors harboring p53 mutations and coincident features of hypoxia, with higher MCT1 levels associated with poorer clinical outcomes. Together, our findings identify MCT1 as a target for p53 repression and they suggest that MCT1 elevation in p53-deficient tumors allows them to adapt to metabolic needs by facilitating lactate export or import depending on the glucose availability.
authors.affiliation: Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pole of Pharmacology, Angiogenesis and Cancer Research Laboratory, Brussels, Belgium.
authors.forename: Romain
authors.initials: R
authors.lastname: Boidot
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Aline
authors.initials: A
authors.lastname: Meulle
authors.forename: Aude
authors.initials: A
authors.lastname: Le Breton
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.forename: Sarab
authors.initials: S
authors.lastname: Lizard-Nacol
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D001692:Biological Transport; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D027981:Symporters; D000097782:NF-kappaB-Inducing Kinase; D000099233:Monocarboxylate Transport Protein 1