The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Open accessAbstract
In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
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LKB1 plays a central role in energy homeostasis by sensing increased intracellular AMP/ATP ratio and phosphorylating AMPK, which in turn suppresses energy consumption by inhibiting mTOR and stimulating autophagy.
“LKB1 plays a central role in energy homeostasis by sensing increased intracellular AMP/ATP ratio and phosphorylating AMPK, which in turn suppresses energy consumption by inhibiting mTOR and stimulating autophagy45.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [45]
In “LKB1 is a master kinase” (page unavailable), the paper says AMPK responds to falling ATP and rising AMP, while LKB1 phosphorylates AMPK during energy stress; it does not say LKB1 itself senses the AMP/ATP ratio. “A LKB1-AMPK-mTORC1 checkpoint” describes AMPK inhibiting mTORC1, and “Outstanding questions” reports that AMPK promotes autophagy under energy-poor conditions. The paper does not establish that autophagy suppresses energy consumption. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAll other signalling components for regulation of mTORC1 depending on energy deprivation sensing and amino acid sensing are present in the tardigrade.
“In contrast, all other signalling components are present for regulation of mTORC1, depending on physiologic demands such as energy deprivation sensing29 and amino acid sensing30.”
From Extremotolerant tardigrade genome and improved radiotolerance of human cultured cells by tardigrade-unique protein (2016) · cites this paper as [29]
LKB1 is a master kinase that regulates diverse cellular processes via phosphorylation of multiple members of AMPK family kinases.
“LKB1 is a master kinase that regulates diverse cellular processes via phosphorylation of multiple members of AMPK family kinases45,65.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [45]
Previous studies have revealed a complex, bidirectional interplay between the Hippo pathway and glucose metabolism.
“previous studies have revealed complex, bidirectional interplay between the Hippo pathway and glucose metabolism (74).”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [74]
Animal experiments have elucidated the mechanisms underlying these epidemiological findings, i.e., interference with glucose, protein, and lipid metabolism of the neoplastic cells.
“and interference with glucose(266), protein(267, 268), and lipid(269) metabolism of the neoplastic cells.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [266]
AMPK activation suppresses mTORC1 activity in response to energetic stress.
“One consequence of AMPK activation is the suppression of mammalian target of rapamycin complex 1 (mTORC1) activity in response to energetic stress (18).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [18]
AMPK antagonizes mRNA translation through negative regulation of mTORC1.
“As mentioned, AMPK antagonizes mRNA translation through negative regulation of mTORC1 (Fig. 4A) (18).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [18]
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References 201 · Cited by 1,943
- Authors
- Shackelford, D. B., & Shaw, R. J.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Shaw, Reuben J.
- Venue
- Nature Reviews Cancer
- Published
- 2009-08
- Volume
- 9
- Issue
- 8
- Pages
- 563-575
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC2756045
- OpenAlex
- W2044874695
- Cited by
- 1,943
- References
- 201
- Citations by year
- 2026: 95 · 2025: 110 · 2024: 117 · 2023: 129 · 2022: 144 · 2021: 151 · 2020: 125 · 2019: 118 · 2018: 112 · 2017: 126 · 2016: 111 · 2015: 129 · 2014: 124 · 2013: 114 · 2012: 106
- FWCI
- 6.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- American Cancer Society
- V Foundation for Cancer Research
- National Institutes of Health
- National Cancer Institute (P01CA120964, T32CA009370)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080425)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- LKB1, AMPK, tumor suppression, cellular metabolism, cell growth regulation, cell polarity, serine/threonine kinase, kinase phosphorylation, glucose metabolism, lipid metabolism, cholesterol metabolism, diabetes drugs, cancer therapy
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Animals, Blood Glucose, Disease Models, Animal, Humans, Hypoglycemic Agents, Neoplasms, Protein Kinases, Signal Transduction, Protein Serine-Threonine Kinases, Protein Kinase Inhibitors, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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