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Sci. Signal., 14 December 2010
Vol. 3, Issue 152, p. ec380
[DOI: 10.1126/scisignal.3152ec380]

EDITORS' CHOICE

Cancer Connecting Signaling and Metabolism in Cancer

L. Bryan Ray

Science, Science Signaling, AAAS, Washington, DC 20005, USA

Attention has recently focused on special properties of metabolism in cancer cells and the possibility that they might be exploited in cancer therapy. Fang et al. provide new insights that help explain the so-called "Warburg effect" in which cancer cells show increased metabolism of glucose by aerobic glycolysis and also link the signaling pathway mediated by phosphoinositide 3-kinase (PI3K) and the protein kinase Akt to the metabolic changes in cancer cells. The phosphatase PTEN acts as a negative regulator of Akt signaling by reversing the effects of PI3K, and loss of PTEN or activation of Akt occurs commonly in human cancers. Fang et al. noted that ATP hydrolysis was more active in mouse embryo fibroblasts from PTEN knockout animals and identified a factor associated with this effect by biochemical purification and mass spectrometry. As it turned out, the enzyme they isolated, ENTPD5 (ectonucleoside triphosphate diphosphohydrolase 5), did not directly account for the effect. Rather, ENTPD5 hydrolyzes uridine diphosphate to uridine monophosphate in the endoplasmic reticulum in a reaction that supports protein folding and N-glycosylation, an action that makes sense for growing cells in which Akt-stimulated protein synthesis is ongoing. Furthermore, ENTPD5 participates in intertwined biochemical cycles that have a net effect of converting ATP to AMP. Such reduction in ATP concentrations relieves inhibition of the rate-limiting enzyme controlling glycolysis and thus can explain the tendency of cancer cells to escape the usual inhibition of glycolysis resulting from accumulation of ATP. Depletion of ENTPD5 from cancer cell lines caused decreased protein glycosylation and reduced surface expression of receptor tyrosine kinases (because they require high amounts of glycosylation) and caused an ER stress response. Loss of ENTPD5 also inhibited growth of such cells as xenografted tumors when transplanted into mice. The authors, and Israelsen and Vander Heiden in commentary, discuss the implications of the results for understanding the coupling of nutrient status and ATP concentrations with expression of growth-promoting receptors and the possibility that pharmacological inhibition of ENTPD5 might provide an effective anticancer therapy.

M. Fang, Z. Shen, S. Huang L. Zhao, S. Chen, T. W. Mak, X. Wang, The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 143, 711–724 (2010). [PubMed]

W. J. Israelsen, M. G. Vander Heiden, ATP consumption promotes cancer metabolism. Cell 143, 669–671 (2010). [PubMed]

Citation: L. B. Ray, Connecting Signaling and Metabolism in Cancer. Sci. Signal. 3, ec380 (2010).



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