AMPK Maintains NADPH Levels during Energy Stress

Cancer cells must adapt to metabolic stressors such as nutrient deprivation and abnormal redox states induced during matrix detachment, anchorage-independent growth, and solid tumor formation in order to survive. AMP-activated protein kinase (AMPK) is activated by liver kinase B1 (LKB1) when intracellular ATP levels are decreased, which is thought to contribute to tumor metabolic adaptation because LKB1- and AMPK-deficient cells are resistant to oncogenic transformation. Jeon and colleagues observed that AMPK is also strongly activated in response to glucose deprivation in an LKB1-independent manner, suggesting that energy stress can activate AMPK through noncanonical mechanisms. Glucose deprivation induces oxidative stress by decreasing production of the reducing agent nicotinamide adenine dinucleotide phosphate (NADPH) in the pentose phosphate pathway. The authors found that AMPK maintained NAPDH levels in the absence of glucose by phosphorylating and inhibiting acetyl CoA carboxylases (ACC) 1 and 2, which increased fatty-acid oxidation and subsequent NADPH generation. ACC inhibition phenocopied AMPK activation and inhibited cell death following glucose deprivation, and constitutive ACC activation blocked fatty-acid oxidation and sensitized tumor cells to cell death in low-glucose conditions. AMPK was also required for ACC-dependent maintenance of NADPH levels during cancer cell matrix detachment and anchorage-independent growth, indicating that AMPK-mediated metabolic adaptation may be critical for cancer cell survival in the early stages of tumor development. Indeed, ACC inhibition stimulated anchorage-independent growth and rescued the ability of AMPK-deficient cells to form tumors. These findings establish redox regulation as an additional function of AMPK and further our understanding of how tumors adapt to energy stress in the solid tumor microenvironment.

Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 2012 May 9 [Epub ahead of print].