Recent studies have highlighted the fact that cancer cells have an altered metabolic phenotype, and this metabolic reprogramming is required to drive the biosynthesis pathways necessary for rapid replication and proliferation. Specifically, the importance of citric acid cycle-generated intermediates in the regulation of cancer cell proliferation has been recently appreciated. One function of MCTs (monocarboxylate transporters) is to transport the citric acid cycle substrate pyruvate across the plasma membrane and into mitochondria, and inhibition of MCTs has been proposed as a therapeutic strategy to target metabolic pathways in cancer. In the present paper, we examined the effect of different metabolic substrates (glucose and pyruvate) on mitochondrial function and proliferation in breast cancer cells. We demonstrated that cancer cells proliferate more rapidly in the presence of exogenous pyruvate when compared with lactate. Pyruvate supplementation fuelled mitochondrial oxygen consumption and the reserve respiratory capacity, and this increase in mitochondrial function correlated with proliferative potential. In addition, inhibition of cellular pyruvate uptake using the MCT inhibitor α-cyano-4-hydroxycinnamic acid impaired mitochondrial respiration and decreased cell growth. These data demonstrate the importance of mitochondrial metabolism in proliferative responses and highlight a novel mechanism of action for MCT inhibitors through suppression of pyruvate-fuelled mitochondrial respiration.
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Research Article|
May 29 2012
Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition
Anne R. Diers;
Anne R. Diers
1Department of Biophysics, Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Katarzyna A. Broniowska;
Katarzyna A. Broniowska
1Department of Biophysics, Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Ching-Fang Chang;
Ching-Fang Chang
1Department of Biophysics, Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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Neil Hogg
Neil Hogg
1
1Department of Biophysics, Redox Biology Program, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
1To whom correspondence should be addressed (email nhogg@mcw.edu).
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Publisher: Portland Press Ltd
Received:
February 15 2012
Revision Received:
March 26 2012
Accepted:
March 30 2012
Accepted Manuscript online:
March 30 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 444 (3): 561–571.
Article history
Received:
February 15 2012
Revision Received:
March 26 2012
Accepted:
March 30 2012
Accepted Manuscript online:
March 30 2012
Citation
Anne R. Diers, Katarzyna A. Broniowska, Ching-Fang Chang, Neil Hogg; Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem J 15 June 2012; 444 (3): 561–571. doi: https://doi.org/10.1042/BJ20120294
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