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Review
. 2018 Jan 1;26(1):39-44.
doi: 10.4062/biomolther.2017.184.

Cancer Energy Metabolism: Shutting Power off Cancer Factory

Soo-Youl Kim  1
Affiliations
Review

Cancer Energy Metabolism: Shutting Power off Cancer Factory

Soo-Youl Kim. Biomol Ther (Seoul). .

Abstract

In 1923, Dr. Warburg had observed that tumors acidified the Ringer solution when 13 mM glucose was added, which was identified as being due to lactate. When glucose is the only source of nutrient, it can serve for both biosynthesis and energy production. However, a series of studies revealed that the cancer cell consumes glucose for biosynthesis through fermentation, not for energy supply, under physiological conditions. Recently, a new observation was made that there is a metabolic symbiosis in which glycolytic and oxidative tumor cells mutually regulate their energy metabolism. Hypoxic cancer cells use glucose for glycolytic metabolism and release lactate which is used by oxygenated cancer cells. This study challenged the Warburg effect, because Warburg claimed that fermentation by irreversible damaging of mitochondria is a fundamental cause of cancer. However, recent studies revealed that mitochondria in cancer cell show active function of oxidative phosphorylation although TCA cycle is stalled. It was also shown that blocking cytosolic NADH production by aldehyde dehydrogenase inhibition, combined with oxidative phosphorylation inhibition, resulted in up to 80% decrease of ATP production, which resulted in a significant regression of tumor growth in the NSCLC model. This suggests a new theory that NADH production in the cytosol plays a key role of ATP production through the mitochondrial electron transport chain in cancer cells, while NADH production is mostly occupied inside mitochondria in normal cells.

Keywords: Cancer energy metabolism; Electron transport chain; Malate-aspartate shuttle; Oxidative phosphorylation; TCA cycle; Warburg effect.

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Figures

Fig. 1.
Fig. 1.
Cancer energy metabolism theories. (A) Classical Warburg effect. Cancer cell adopts oxygenated glycolysis. (B) Cancer cell symbiosis. The fate of lactate remains to be clarified in the energy metabolism. TCA: tri-carboxylic acid cycle (Kreb’s cycle), ETC: electron transport chain.
Fig. 2.
Fig. 2.
Two experiments related with cancer energy metabolism. (A) ALDH1L1 in one-carbon pathway produces abundant cytosolic NADH which generates ATP following to transport to mitochondria via MAS in NSCLC. By combined inhibition of ALDH and mitochondrial complex I, xenograft cancer model showed significant regression of tumor growth (Kang et al., 2016b). (B) GLS1 supplies abundant glutamate for MAS to produce ATP that is needed for pyrimidine synthesis in NSCLC. By combined inhibition of GLS1 and TYMS, xenograft cancer model showed significant regression of tumor growth (Lee et al., 2016a). THF: tetrahydrofolate, GLS1: glutaminase 1, TYMS: thymidylate synthetase, ALDH: aldehyde dehydrogenase, CPSII: carbamoylphosphate synthase II, *: ATP sensitive enzyme, MAS: malate aspartate shuttle, ETC: electron transfer complex, BPTES: bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide.
Fig. 3.
Fig. 3.
A new proposed model of cancer energy metabolism. Major source of electron may be cytosolic NADH produced by metabolic enzymes such as ALDH. ETC: electron transport chain, FAO: fatty acid oxidation, MAS: malate-aspartate shuttle, TCA: tri-carboxylic acid cycle.
Fig. 4.
Fig. 4.
Anti-cancer therapeutic approach. (A) Targeting cancer translation by targeting signaling molecules such as receptor tyrosine kinases and mTOR. (B) Targeting cancer energy metabolism by regulating energy supplies such as cytosolic NADH producing enzymes, ETC and MAS. ETC: electron transport chain, MAS: malate-aspartate shuttle.
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References

    1. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer. 2013;13:227–232. doi: 10.1038/nrc3483. - DOI - PMC - PubMed
    1. Chandel NS, Budinger GR, Choe SH, Schumacker PT. Cellular respiration during hypoxia. Role of cytochrome oxidase as the oxygen sensor in hepatocytes. J Biol Chem. 1997;272:18808–18816. doi: 10.1074/jbc.272.30.18808. - DOI - PubMed
    1. Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, Wa Cheng K, Hall H, Zhang D, Lu Y, Ravoori M, Kundra V, Ajani J, Lee JS, Ki Hong W, Mills GB. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther. 2011;10:2350–2362. doi: 10.1158/1535-7163.MCT-11-0497. - DOI - PMC - PubMed
    1. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20. doi: 10.1016/j.cmet.2007.10.002. - DOI - PubMed
    1. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. 2007;104:19345–19350. doi: 10.1073/pnas.0709747104. - DOI - PMC - PubMed

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