title: Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H(+) symporters.
abstract: Since Otto Warburg reported the 'addiction' of cancer cells to fermentative glycolysis, a metabolic pathway that provides energy and building blocks, thousands of studies have shed new light on the molecular mechanisms contributing to altered cancer metabolism. Hypoxia, through hypoxia-inducible factors (HIFs), in addition to oncogenes activation and loss of tumour suppressors constitute major regulators of not only the "Warburg effect" but also many other metabolic pathways such as glutaminolysis. Enhanced glucose and glutamine catabolism has become a recognised feature of cancer cells, leading to accumulation of metabolites in the tumour microenvironment, which offers growth advantages to tumours. Among these metabolites, lactic acid, besides imposing an acidic stress, is emerging as a key signalling molecule that plays a pivotal role in cancer cell migration, angiogenesis, immune escape and metastasis. Although interest in lactate for cancer development only appeared recently, pharmacological molecules blocking its metabolism are already in phase I/II clinical trials. Here, we review the metabolic pathways generating lactate, and we discuss the rationale for targeting lactic acid transporter complexes for the development of efficient and selective anticancer therapies.
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Centre A. Lacassagne, 33 Avenue, 06189, Nice, France.
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Marchiq
authors.affiliation: Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice Sophia Antipolis, Centre A. Lacassagne, 33 Avenue, 06189, Nice, France. pouysseg@unice.fr.|Medical Biology Department (CSM), Centre Scientifique de Monaco, Quai Antoine 1er, Monaco. pouysseg@unice.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051926:Basigin / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D058990:Molecular Targeted Therapy; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D040081:Protein Array Analysis; D055503:Protein Multimerization; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497886:BSG protein, human; D015415:Biomarkers; D027501:Monocarboxylic Acid Transporters; D046912:Multiprotein Complexes; D051926:Basigin; D019344:Lactic Acid
keywords: BASIGIN; Cancer; Lactate; MCT; Monocarboxylate Transporters; Therapy; Warburg effect