AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress

By Sang-Min Jeon, Navdeep S. Chandel, N. Hay. Nature, 2012

1,105 citations recorded by the source corpus.

Overcoming metabolic stress is a critical step for solid tumour growth. However, the underlying mechanisms of cell death and survival under metabolic stress are not well understood. A key signalling pathway involved in metabolic adaptation is the liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK) pathway. Energy stress conditions that decrease intracellular ATP levels below a certain level promote AMPK activation by LKB1. Previous studies showed that LKB1-deficient or AMPK-deficient cells are resistant to oncogenic transformation and tumorigenesis, possibly because of the function of AMPK in metabolic adaptation. However, the mechanisms by which AMPK promotes metabolic adaptation in tumour cells are not fully understood. Here we show that AMPK activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 and ACC2 by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty-acid synthesis and increasing NADPH generation by means of fatty-acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumour formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth and solid tumour formation in vivo.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/99133049251ee1efbdc6466c186fee2c8498756e

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Citations in the corpus

Targeting Metabolism for Cancer Therapy (2017, background): “For example, while targeting ACC to limit fatty synthesis can suppress lung tumor progression in some models (Svensson et al., 2016), loss of ACC activity can accelerate tumor growth in other cancer models (Jeon et al., 2012).”
Oxidative Stress in Cancer (2020, background): “, 2009), while detachment of human A549 non-small cell lung cancer cells increases H2O2 and decreases NADPH levels (Jeon et al., 2012).”
Role of PFKFB3-driven glycolysis in vessel sprouting. (2013, positive): “In conditions of stress, PFKFB3-silenced ECs even increased fatty acid oxidation (Figure 7P), likely to ensure redox homeostasis (Jeon et al., 2012).”
Fundamentals of cancer metabolism (2016, background): “Cells in these nutrient-deprived conditions activate AMPK to increase NADPH levels by stimulating PPPdependent NADPH and diminishing anabolic pathways, such as lipid synthesis, that require high levels ofNADPH(134,135).”
AMPK is a negative regulator of the Warburg Effect and suppresses tumor growth in vivo (2012, background): “AMPK activity has been recently linked to stress resistance and survival in tumor cells (Jeon et al., 2012; Liu et al., 2012).”
Co-occurring genomic alterations define major subsets of KRAS - mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities (2015, neutral): “Increased generation of reactive oxygen species (ROS) from cells undergoing energetic stress, coupled with defective H2O2 detoxification due to impaired NADPH maintenance, may provide the impetus for this adaptive response (41, 42).”
Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “In a reverse process, LKB1/AMPK activation under energy stress reduces NADPH consumption by repressing fatty acid synthesis and enhancing NADPH generation from the oxidation of preexisting fatty acids to maintain ROS homeostasis (92).”