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

Joanne R. Doherty, Chunying Yang, Kristen E N Scott, Michael D. Cameron, Mohammad Fallahi, Weimin Li, Mark A. Hall, Antonio L. Amelio, Jitendra K. Mishra, Fangzheng Li, Mariola Tortosa, Heide Marika Genau, Robert J. Rounbehler, Yunqi Lu, Chi V. Dang, K. Ganesh Kumar, Andrew A. Butler, Thomas D. Bannister, Andrea T. Hooper, Keziban Unsal-KacmazWilliam R. Roush, John L. Cleveland

Research output: Contribution to journalArticle

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 Em-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.

Original languageEnglish (US)
Pages (from-to)908-920
Number of pages13
JournalCancer Research
Volume74
Issue number3
DOIs
StatePublished - Feb 1 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Doherty, J. R., Yang, C., Scott, K. E. N., Cameron, M. D., 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, A. A., Bannister, T. D., Hooper, A. T., ... Cleveland, J. L. (2014). Blocking lactate export by inhibiting the myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Research, 74(3), 908-920. https://doi.org/10.1158/0008-5472.CAN-13-2034