title: Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis.
abstract: Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.
authors.affiliation: Authors' Affiliations: Departments of Cancer Biology, Chemistry, and Metabolism and Aging; The Translational Research Institute, The Scripps Research Institute, Scripps Florida, Jupiter, Florida; Institute of Biochemistry II, Goethe University Medical School, Frankfurt am Main, Germany; Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; and Pfizer Oncology, Pearl River, New Jersey.
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Doherty
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.forename: Kristen E N
authors.initials: KE
authors.lastname: Scott
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hall
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Amelio
authors.forename: Jitendra K
authors.initials: JK
authors.lastname: Mishra
authors.forename: Fangzheng
authors.initials: F
authors.lastname: Li
authors.forename: Mariola
authors.initials: M
authors.lastname: Tortosa
authors.forename: Heide Marika
authors.initials: HM
authors.lastname: Genau
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rounbehler
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Lu
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: K Ganesh
authors.initials: KG
authors.lastname: Kumar
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Butler
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bannister
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: Keziban
authors.initials: K
authors.lastname: Unsal-Kacmaz
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000096:biosynthesis*; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D005978:Glutathione; D006861:Hydrogen Peroxide; D019344:Lactic Acid; D008687:Metformin; D027501:Monocarboxylic Acid Transporters; D016271:Proto-Oncogene Proteins c-myc; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1