Research Papers:
Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model
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Abstract
Dudley W. Lamming1,2,3,*, Nicole E. Cummings1,2,3, Antonella L. Rastelli4, Feng Gao5, Edda Cava6,7, Beatrice Bertozzi6, Francesco Spelta6,8, Roberto Pili9, Luigi Fontana6,10,11,*
1Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
2William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
3Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA
4Division of Oncology, Washington University in St. Louis, MO, USA
5Division of Biostatistics, Washington University in St. Louis, MO, USA
6Division of Geriatrics and Nutritional Sciences, Washington University in St. Louis, MO, USA
7Department of Experimental Medicine, University of Rome “La Sapienza”, Italy
8Department of Medicine, University of Verona, Italy
9Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
10Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, Italy
11CEINGE 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, 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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