Loss of the Tumor Suppressor LKB1 Promotes Metabolic Reprogramming of Cancer Cells via HIF-1α
Open accessAbstract
One of the major metabolic changes associated with cellular transformation is enhanced nutrient utilization, which supports tumor progression by fueling both energy production and providing biosynthetic intermediates for growth. The liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor that couples bioenergetics to cell-growth control through regulation of mammalian target of rapamycin (mTOR) activity; however, the influence of LKB1 on tumor metabolism is not well defined. Here, we show that loss of LKB1 induces a progrowth metabolic program in proliferating cells. Cells lacking LKB1 display increased glucose and glutamine uptake and utilization, which support both cellular ATP levels and increased macromolecular biosynthesis. This LKB1-dependent reprogramming of cell metabolism is dependent on the hypoxia-inducible factor-1α (HIF-1α), which accumulates under normoxia in LKB1-deficient cells and is antagonized by inhibition of mTOR complex I signaling. Silencing HIF-1α reverses the metabolic advantages conferred by reduced LKB1 signaling and impairs the growth and survival of LKB1-deficient tumor cells under low-nutrient conditions. Together, our data implicate the tumor suppressor LKB1 as a central regulator of tumor metabolism and growth control through the regulation of HIF-1α-dependent metabolic reprogramming.
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LKB1 is a tumor suppressor and mutations in LKB1 are observed in numerous cancers that reduce the inhibitory effect of the LKB1/AMPK pathway on pro-proliferative signaling via mTOR.
“LKB1 is a tumor suppressor and that mutations in LKB1 are observed in numerous cancers that result in the reduction of the inhibitory effect of the LKB1/AMPK pathway on the pro-proliferative signaling via mTOR (125, 126).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [125]
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“This metabolic reprogramming is induced by increased hypoxia-inducible factor-1α (HIF-1α) protein stabilization under normoxia conditions and targeting HIF-1α impairs growth and survival of LKB1 deficient cells [69, 71].”
BackgroundLKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
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- Authors
- Faubert, B., Vincent, E. E., Griss, T., Samborska, B., Izreig, S., Svensson, R. U., Mamer, O. A., Avizonis, D., Shackelford, D. B., Shaw, R. J., & Jones, R. G.
- Affiliations
- McGill University (CA)
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3;
- Salk Institute for Biological Studies (US)
- University of California, Los Angeles (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-02-03
- Volume
- 111
- Issue
- 7
- Pages
- 2554-2559
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3932920
- OpenAlex
- W2071944097
- Cited by
- 278
- References
- 42
- Citations by year
- 2026: 19 · 2025: 14 · 2024: 36 · 2023: 31 · 2022: 22 · 2021: 24 · 2020: 20 · 2019: 18 · 2018: 24 · 2017: 28 · 2016: 12 · 2015: 22 · 2014: 7
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Canadian Institutes of Health Research (MOP-93 799)
- National Cancer Institute (P01CA120964)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- LKB1, tumor suppressor, metabolic reprogramming, HIF-1α, glucose uptake, glutamine uptake, cancer metabolism, cell growth regulation, hypoxia, nutrient utilization, macromolecular synthesis
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, AMP-Activated Protein Kinase Kinases, Adenosine Triphosphate, Analysis of Variance, Animals, Energy Metabolism, Fibroblasts, Glucose, Glutamine, Humans, Gas Chromatography-Mass Spectrometry, Oxygen Consumption, Blotting, Western, Apoptosis, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Cell Line, Tumor, Multiprotein Complexes, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Metabolic Networks and Pathways, TOR Serine-Threonine Kinases
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