TY - JOUR
T1 - Blocking lactate export by inhibiting the myc target MCT1 disables glycolysis and glutathione synthesis
AU - Doherty, Joanne R.
AU - Yang, Chunying
AU - Scott, Kristen E N
AU - Cameron, Michael D.
AU - Fallahi, Mohammad
AU - Li, Weimin
AU - Hall, Mark A.
AU - Amelio, Antonio L.
AU - Mishra, Jitendra K.
AU - Li, Fangzheng
AU - Tortosa, Mariola
AU - Genau, Heide Marika
AU - Rounbehler, Robert J.
AU - Lu, Yunqi
AU - Dang, Chi V.
AU - Kumar, K. Ganesh
AU - Butler, Andrew A.
AU - Bannister, Thomas D.
AU - Hooper, Andrea T.
AU - Unsal-Kacmaz, Keziban
AU - Roush, William R.
AU - Cleveland, John L.
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84893860311&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-2034
DO - 10.1158/0008-5472.CAN-13-2034
M3 - Article
C2 - 24285728
AN - SCOPUS:84893860311
VL - 74
SP - 908
EP - 920
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 3
ER -