title: CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.
abstract: Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H(+)/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res(-)) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res(-) cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, highlighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H(+) symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin(high) cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy.
authors.affiliation: Institute of Developmental Biology and Cancer, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6543,  University of Nice, 06189 Nice,  France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Le Floch
authors.forename: Johanna
authors.initials: J
authors.lastname: Chiche
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Marchiq
authors.forename: Tanesha
authors.initials: T
authors.lastname: Naiken
authors.forename: Tanesha
authors.initials: T
authors.lastname: Naïken
authors.forename: Karine
authors.initials: K
authors.lastname: Ilc
authors.forename: Karine
authors.initials: K
authors.lastname: Ilk
authors.forename: Clare M
authors.initials: CM
authors.lastname: Murray
authors.forename: Susan E
authors.initials: SE
authors.lastname: Critchlow
authors.forename: Danièle
authors.initials: D
authors.lastname: Roux
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Simon
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
mesh_terms: D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D051926:Basigin; D017931:DNA Primers; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D021122:Protein Subunits; D027981:Symporters; D013876:Thiophenes; D014498:Uracil; D000099233:Monocarboxylate Transport Protein 1; C546977:AR C155858; C406962:SLC16A4 protein, human