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Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis

Academic Article
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Overview

authors

  • Doherty, J. R.
  • Yang, C.
  • Scott, K. E. N.
  • Cameron, Michael
  • Fallahi, M.
  • Li, W.
  • Hall, M. A.
  • Amelio, A. L.
  • Mishra, J. K.
  • Li, F.
  • Tortosa, M.
  • Genau, H. M.
  • Rounbehler, R. J.
  • Lu, Y.
  • Dang, C. V.
  • Kumar, K. G.
  • Butler, Andrew
  • Bannister, Thomas
  • Hooper, A. T.
  • Unsal-Kacmaz, K.
  • Roush, William
  • Cleveland, John

publication date

  • February 2014

journal

  • Cancer Research  Journal

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 E?-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.
  • 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.

subject areas

  • Animals
  • Cell Death
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cluster Analysis
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glutathione
  • Glycolysis
  • Homeostasis
  • Humans
  • Hydrogen Peroxide
  • Lactic Acid
  • Metformin
  • Mice
  • Monocarboxylic Acid Transporters
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-myc
  • Symporters
  • Transcription, Genetic
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Identity

PubMed Central ID

  • PMC3946415

International Standard Serial Number (ISSN)

  • 0008-5472

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.can-13-2034

PubMed ID

  • 24285728
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Additional Document Info

start page

  • 908

end page

  • 920

volume

  • 74

issue

  • 3

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