Tumours with PI3K activation are resistant to dietary restriction
Open accessAbstract
Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies.
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Certain experimental cancers tend to behave more aggressively when animals overeat and less aggressively when animals are calorically restricted.
“Certain experimental cancers tend to behave more aggressively when animals overeat and less aggressively when animals are calorically restricted (72–74).”
From Diabetes and Cancer (2010) · cites this paper as [72]
Animal studies of energy balance support epidemiologic results relating obesity with cancer mortality.
“Similarly, animal studies of energy balance support epidemiologic results relating obesity with cancer mortality.”
From Diabetes and Cancer (2010) · cites this paper as [72]
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- Authors
- Kalaany, N. Y., & Sabatini, D. M.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Broad Institute (US)
- Corresponding author
- Sabatini, David M.
- Venue
- Nature
- Published
- 2009-03-11
- Volume
- 458
- Issue
- 7239
- Pages
- 725-731
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2692085
- OpenAlex
- W2072301671
- Cited by
- 468
- References
- 38
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 17 · 2023: 20 · 2022: 12 · 2021: 24 · 2020: 33 · 2019: 24 · 2018: 22 · 2017: 36 · 2016: 28 · 2015: 24 · 2014: 32 · 2013: 44 · 2012: 34
- FWCI
- 17.30
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-04-30)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA103866, R01CA129105)
- National Institute of Allergy and Infectious Diseases (R01AI047389, R01 AI04389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- dietary restriction, PI3K/Akt signaling, tumor growth, PTEN, FOXO1, insulin-like growth factor I, PI3K mutations, tumor xenografts, lung cancer, prostate cancer, tumor cell proliferation
- MeSH terms
- Forkhead Box Protein O1, Animals, Enzyme Activation, Female, Humans, Male, Neoplasms, Transplantation, Heterologous, Signal Transduction, Gene Expression, Mice, SCID, Mice, Inbred NOD, Apoptosis, Phosphatidylinositol 3-Kinases, Caloric Restriction, Cell Line, Tumor, PTEN Phosphohydrolase, Mice, Forkhead Transcription Factors
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