Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model
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// Dudley W. Lamming 1, 2, 3, * , Nicole E. Cummings 1, 2, 3 , Antonella L. Rastelli 4 , Feng Gao 5 , Edda Cava 6, 7 , Beatrice Bertozzi 6 , Francesco Spelta 6, 8 , Roberto Pili 9 , Luigi Fontana 6, 10, 11, * 1 Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA 2 William S. Middleton Memorial Veterans Hospital, Madison, WI, USA 3 Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA 4 Division of Oncology, Washington University in St. Louis, MO, USA 5 Division of Biostatistics, Washington University in St. Louis, MO, USA 6 Division of Geriatrics and Nutritional Sciences, Washington University in St. Louis, MO, USA 7 Department of Experimental Medicine, University of Rome “La Sapienza”, Italy 8 Department of Medicine, University of Verona, Italy 9 Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 10 Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, Italy 11 CEINGE Biotecnologie Avanzate, Napoli, Italy * These authors have contributed equally to this work Correspondence to: Luigi Fontana, e-mail: fontana.luigi@gmail.com Dudley W. Lamming, e-mail: dlamming@medicine.wisc.edu Keywords: protein restriction, mTOR, mice, cancer, aging Received: June 21, 2015 Accepted: August 20, 2015 Published: September 03, 2015 ABSTRACT Reduced dietary protein intake and intermittent fasting (IF) are both linked to healthy longevity in rodents, and are effective in inhibiting cancer growth. The molecular mechanisms underlying the beneficial effects of chronic protein restriction (PR) and IF are unclear, but may be mediated in part by a down-regulation of the IGF/mTOR pathway. In this study we compared the effects of PR and IF on tumor growth in a xenograft mouse model of breast cancer. We also investigated the effects of PR and IF on the mechanistic Target Of Rapamycin (mTOR) pathway, inhibition of which extends lifespan in model organisms including mice. The mTOR protein kinase is found in two distinct complexes, of which mTOR complex 1 (mTORC1) is responsive to acute treatment with amino acids in cell culture and in vivo . We found that both PR and IF inhibit tumor growth and mTORC1 phosphorylation in tumor xenografts. In somatic tissues, we found that PR, but not IF, selectively inhibits the activity of the amino acid sensitive mTORC1, while the activity of the second mTOR complex, mTORC2, was relatively unaffected by PR. In contrast, IF resulted in increased S6 phosphorylation in multiple metabolic tissues. Our work represents the first finding that PR may reduce mTORC1 activity in tumors and multiple somatic tissues, and suggest that PR may represent a highly translatable option for the treatment not only of cancer, but also other age-related diseases.
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Isocaloric restriction of protein or substitution of plant for animal proteins markedly inhibits prostate and breast cancer growth in human xenograft animal models of cancer, with reduced serum IGF-1 levels and downregulation of mTOR activity in the tumor and normal tissue.
“Moreover, it has been shown that isocaloric restriction of protein or substitution of plant for animal proteins markedly inhibits prostate and breast cancer growth in human xenograft animal models of cancer, with reduced serum IGF-1 levels and downregulation of the mechanistic target of rapamycin (mTOR) activity in the tumor and normal tissue as well (74).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [74]
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Nutritional modulation of antitumor immunity
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- Authors
- Lamming, D. W., Cummings, N. E., Rastelli, A. L., Gao, F., Cava, E., Bertozzi, B., Spelta, F., Pili, R., & Fontana, L.
- Affiliations
- University of Wisconsin–Madison (US)
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Washington University in St. Louis (US)
- University of Verona (IT)
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Corresponding author
- Lamming, Dudley W.
- Fontana, Luigi
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-09-03
- Volume
- 6
- Issue
- 31
- Pages
- 31233-31240
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4741600
- OpenAlex
- W2147270926
- Cited by
- 69
- References
- 35
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 10 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 6 · 2016: 6 · 2015: 1
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (AG041765)
- National Institute on Aging (R00AG041765, K99AG041765, AG041765)
- National Cancer Institute (P30CA091842)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341)
- 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 › Cell Biology › Muscle metabolism and nutrition
- Keywords
- protein restriction, intermittent fasting, mTORC1, breast cancer, tumor growth, somatic tissues, aging, longevity, rapamycin, insulin-like growth factor I, insulin-like growth factor II, mTOR signaling, tumor microenvironment, tumor vasculature
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Animals, Breast Neoplasms, Dietary Proteins, Female, Humans, Phosphorylation, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Inbred NOD, Xenograft Model Antitumor Assays, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases
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