Editors' ChoiceCancer

Metabolic Gatekeeper

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Sci. Signal.  29 Jan 2013:
Vol. 6, Issue 260, pp. ec27
DOI: 10.1126/scisignal.2004003

Under aerobic conditions, cancer cells use glycolysis to produce energy in the form of adenosine triphosphate (ATP) from glucose, with lactate as a by-product, a phenomenon known as the Warburg effect. This metabolic shift is believed to give cancer cells an advantage over normal noncancerous cells. Various cancers are functionally deficient in adenosine monophosphate (AMP)–activated protein kinase (AMPK), which acts as an energy sensor. Faubert et al. investigated the role of AMPK in tumorigenesis, tumor metabolism, and tumor progression. Eμ-Myc mice overexpress the oncogene c-Myc and are a model for lymphomagenesis. Eμ-Myc mice that also had an inactivating mutation in the α1 catalytic subunit of AMPK (Eμ-Myc/α1–/– mice) developed lymphomagenesis more quickly and had a lower survival rate compared with Eμ-Myc mice. In vitro competition assays demonstrated that Eμ-Myc lymphoma cells transduced with an shRNA directed against AMPKα1 had a proliferative advantage over those transduced with a control shRNA. Metabolomic analysis revealed decreased glucose concentrations and increased lactate concentrations in AMPKα1 shRNA-expressing Eμ-Myc lymphomas, which also showed increased extracellular acidification rate (ECAR; an index of lactate production) but no change in the rate of oxygen consumption. Lactate production and ECAR were also increased in non–small cell lung carcinoma H1299 cells and colon carcinoma HCT116 cells expressing shRNAs directed against the α1 and α2 subunits of AMPK. Mouse embryonic fibroblasts (MEFs) lacking AMPKα converted glucose to lactate at a higher rate, produced higher concentrations of citrate (which is derived from glucose and shunted into lipid biosynthesis), and were larger in size than control MEFs. AMPKα-deficient MEFs and AMPKα1 shRNA-expressing Eμ-Myc lymphoma cells showed greater abundance of aldolase, lactate dehydrogenase A, and pyruvate dehydrogenase kinase 1, all of which are glycolytic enzymes. In addition, the genes encoding these enzymes are transcriptional targets of hypoxia-inducible factor (HIF)–1α. This transcription factor is usually low in abundance under normal oxygen tensions (normoxia); however, its abundance was increased in AMPKα-deficient MEFs, Eμ-Myc lymphoma cells, and H1299 cells under normoxic conditions. Silencing HIF-1α in AMPKα-deficient MEFs reduced ECAR; glucose consumption; production of pyruvate, lactate, and citrate; lipid biosynthesis; and proliferation to that seen in control MEFs or lower. The increase in the abundance of aldolase and lactate dehydrogenase A, ECAR, and proliferation in AMPKα1 shRNA-expressing Eμ-Myc lymphoma cells was attenuated by stable expression of a HIF-1α shRNA. When injected into mice, fewer Eμ-Myc lymphoma cells expressing both AMPKα1 and HIF-1α shRNAs were recovered compared with Eμ-Myc lymphoma cells with AMPKα1 or that only expressed the AMPKα1 shRNA, indicating that silencing HIF-1α counteracted the proliferative advantage conferred by silencing of AMPKα1. The authors propose that AMPK restrains metabolic and biosynthetic pathways required to support uncontrolled proliferation.

B. Faubert, G. Boily, S. Izreig, T. Griss, B. Samborska, Z. Dong, F. Dupuy, C. Chambers, B. J. Fuerth, B. Viollet, O. A. Mamer, D. Avizonis, R. J. DeBerardinis, P. M. Siegel, R. G. Jones, AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17, 113–124 (2013). [PubMed]

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