title: Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model.
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.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.|Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Dudley W
authors.initials: DW
authors.lastname: Lamming
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.|William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.|Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Cummings
authors.affiliation: Division of Oncology, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Antonella L
authors.initials: AL
authors.lastname: Rastelli
authors.affiliation: Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Washington University in St. Louis, MO, USA.|Department of Experimental Medicine, University of Rome "La Sapienza", Sapienza, Italy.
authors.forename: Edda
authors.initials: E
authors.lastname: Cava
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Washington University in St. Louis, MO, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bertozzi
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Washington University in St. Louis, MO, USA.|Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Spelta
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Washington University in St. Louis, MO, USA.|Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, Italy.|CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Fontana
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000178:diet therapy* / Q000378:metabolism* / Q000473:pathology; D004044:Dietary Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004044:Dietary Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: aging; cancer; mTOR; mice; protein restriction