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Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

Key Points

  • Cancer cells display high aerobic glycolysis despite oxidative phosphorylation.

  • High aerobic glycolysis distinguishes cancer cells from normal cells, and is exploited to detect tumours in vivo.

  • Cancer cells increase glucose flux to meet anabolic demands and to maintain the redox state.

  • Cancer cells preferentially express transporters and enzyme isoforms that drive glucose flux forwards.

  • Selective targeting of glucose metabolism for cancer therapy is challenging, but possible.

  • As a proof of concept, hexokinase 2 (HK2), which is preferentially expressed by cancer cells, can be systemically deleted in mice for cancer therapy and without adverse consequences.

  • It is possible that in the future, targeting glucose metabolism will be used as adjuvant therapy together with existing cancer therapeutic approaches.

Abstract

In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells.

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Figure 1: Changes that occur in glucose metabolism of cancer cells.
Figure 2: Branching pathways from glucose-6-phosphate.
Figure 3: The serine biosynthesis pathway and extensions to the one-carbon metabolism, the methionine cycle, the purine biosynthesis pathway and the generation of glutathione.
Figure 4: Positive and negative regulation of enzymes in glucose metabolism.
Figure 5: Regulation of glucose metabolism by oncoproteins and tumour suppressors.
Figure 6: Reprogramming of glucose metabolism in hepatocellular carcinoma.
Figure 7: Energetic and oxidative stress during solid tumour formation.

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Acknowledgements

The work is supported by grants CA090764, and AG016927 from the National Institutes of Health and by a Veteran Affairs Merit Award BX000733 to N.H.

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Glossary

Aerobic glycolysis

Conversion of glucose into lactate that takes place in the presence of oxygen.

Oxidative phosphorylation

(OXPHO). A metabolic process of nutrient oxidation that generates ATP in mitochondria.

Pentose phosphate pathway

(PPP). A metabolic process in which glucose is used to generate NADPH and ribose-5-phosphate for nucleotide biosynthesis.

Hexosamine pathway

A metabolic process in which an amine group is added to hexoses to generate a sugar donor for the glycosylation of proteins.

One-carbon metabolism

Biochemical reactions catalysed by a set of enzymes and coenzymes in which the transfer of one-carbon groups occurs to provide precursors for purine synthesis and the methionine cycle.

Tricarboxylic acid cycle

(TCA cycle). A series of chemical reactions that start with oxidation of acetyl-CoA to generate precursors for certain amino acids and a reducing agent for oxidative phosphorylation.

Folate cycle

A metabolic pathway, included in one-carbon metabolism, that uses tetrahydrofolates as cofactors and precursors for purine synthesis and the methionine cycle.

Methionine cycle

Part of one-carbon metabolism, the methionine cycle generates S-adenosylmethionine, which is a substrate for methyltransferases.

Hypoglycorrhachia

An abnormally low glucose level in the cerebrospinal fluid.

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Hay, N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?. Nat Rev Cancer 16, 635–649 (2016). https://doi.org/10.1038/nrc.2016.77

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