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Sci. Signal., 5 June 2012
Vol. 5, Issue 227, p. ec156
[DOI: 10.1126/scisignal.2003284]

EDITORS' CHOICE

Metabolism The NADPH Survival Advantage

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Under conditions of metabolic stress that lead to a decrease in the intracellular concentration of adenosine triphosphate (ATP), liver kinase B1 (LKB1) is activated, which in turn phosphorylates and activates adenosine monophosphate (AMP)–activated protein kinase (AMPK), which modulates glucose metabolism and autophagy in the cell to promote energy homeostasis. The LKB1-AMPK signaling pathway is also activated in tumor cells in response to certain oncogenes and as a result of the detachment of cells from the extracellular matrix. Noting that cells deficient in LKB1 or AMPK are resistant to oncogenic transformation, Jeon et al. investigated how AMPK modulated metabolism in tumor cells. A549 cells, a human epithelial cancer cell line deficient in LKB1, were more sensitive than LKB1-sufficient cell lines to cell death induced by glucose deprivation. In addition, LKB1-deficient cells exhibited increased NADPH depletion and oxidative stress during glucose deprivation compared with LKB1-sufficient cells. NADPH is consumed by fatty acid synthesis (FAS) and generated through fatty acid oxidation (FAO). NAPDH reduces oxidative stress in cells by detoxifying hydrogen peroxide. AMPK phosphorylates and inhibits the enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2, thereby inhibiting FAS and increasing FAO. The authors found that knockdown of ACC1 or ACC2 substantially inhibited A549 cell death induced by glucose deprivation. Additionally, AMPK activation was required for the inhibition of the ACCs and for the maintenance of NAPDH abundance in cells during conditions of glucose deprivation or matrix detachment. Tumor growth in mice injected with oncogenic fibroblasts expressing mutant ACC isoforms that could not be phosphorylated by AMPK was reduced compared to that in mice injected with control tumor cells. Together, these data suggest that under conditions of metabolic stress, AMPK maintains NAPDH concentrations in tumor cells to reduce oxidative stress and promote survival. As Svensson and Shaw discuss in commentary, future work will determine how the timing and context of LKB1-AMPK signaling determine tumor cell survival.

S.-M. Jeon, N. S. Chandel, N. Hay, AMPK regulates NAPDH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012). [Online Journal]

R. U. Svensson, R. J. Shaw, Tumour friend or foe. Nature 485, 590–591 (2012). [Online Journal]

Citation: J. F. Foley, The NADPH Survival Advantage. Sci. Signal. 5, ec156 (2012).



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