AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress
Open accessAbstract
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.
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Targeting ACC to limit fatty acid synthesis can suppress lung tumor progression in some models, but loss of ACC activity can accelerate tumor growth in other cancer models.
“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).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Jeon et al., 2012
Potentiation of cellular anabolic, antioxidant and detoxification pathways collectively support the aggressive clinical phenotype of KEAP1-mutant NSCLC, concordant with its role as an independent negative prognostic indicator.
“Potentiation of cellular anabolic, antioxidant and detoxification pathways collectively support the aggressive clinical phenotype of KEAP1-mutant NSCLC that is concordant with its role as an independent negative prognostic indicator92, 99.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [99]
In KRAS-mutant LUAD, KEAP1 co-mutations predict markedly poorer outcomes after platinum-doublet chemotherapy.
“significantly worse clinical outcomes with platinum-doublet chemotherapy in KRAS-mutant LUAD99”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [99]
KEAP1 co-mutations have been linked to de novo resistance against PD-1 blockade.
“co-mutations in KEAP1 have also been implicated in de novo resistance to PD-1 blockade99”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [99]
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LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
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“LKB1 is a master serine/threonine kinase that regulates multiple cellular process including growth 26,35 , cell metabolism 20,21 , and cell polarity 36 – 38 .”
- Authors
- Jeon, S.-M., Chandel, N. S., & Hay, N.
- Affiliations
- University of Illinois Chicago (US)
- Northwestern University (US)
- Corresponding author
- Hay, Nissim
- Venue
- Nature
- Published
- 2012-05
- Volume
- 485
- Issue
- 7400
- Pages
- 661-665
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3607316
- OpenAlex
- W2023947368
- Cited by
- 1,132
- References
- 36
- Citations by year
- 2026: 47 · 2025: 58 · 2024: 82 · 2023: 57 · 2022: 82 · 2021: 107 · 2020: 105 · 2019: 93 · 2018: 83 · 2017: 90 · 2016: 90 · 2015: 80 · 2014: 84 · 2013: 57 · 2012: 16
- FWCI
- 30.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (AG 025953, R01AG025953, R01AG016927, AG016927)
- National Cancer Institute (CA090764, R01CA090764)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60DK20595, P60DK020595)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- AMPK, LKB1, tumor cell survival, energy stress, metabolic stress, acetyl-CoA carboxylase, acetyl-CoA carboxylase 1, acetyl-CoA carboxylase 2, fatty acid synthesis, fatty acid oxidation, pentose phosphate pathway, redox regulation, anchorage-independent growth, tumor growth, carcinogenesis, glucose limitation
- MeSH terms
- Acetyl-CoA Carboxylase, Animals, Cell Survival, Cell Transformation, Neoplastic, Contact Inhibition, Energy Metabolism, Enzyme Activation, Female, Glucose, Cricetinae, Homeostasis, Hydrogen Peroxide, Male, Mice, Nude, NADP, Neoplasms, Oxidation-Reduction, CHO Cells, Cell Death, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Oxidative Stress, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases
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