Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model

// 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: [email protected] Dudley W. Lamming, e-mail: [email protected] Keywords: protein restriction, mTOR(definition), 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(definition) (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.