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. 2015 Oct 13;6(31):31233-40.
doi: 10.18632/oncotarget.5180.

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
Affiliations

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

Dudley W Lamming et al. Oncotarget. .

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.

Keywords: aging; cancer; mTOR; mice; protein restriction.

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Conflict of interest statement

CONFLICTS OF INTEREST

None of the authors had conflicts of interest.

Figures

Figure 1
Figure 1. A low protein diet or intermittent fasting regimen slows tumor growth rate in a mouse model of breast cancer
A. Weights of 6 week old female mice placed on diets containing either 21% or 7% protein, which were fed either ad libitum (AL) or with intermittent, alternate day fasting (IF). Arrow indicates time of tumor implantation on day 29. B. Tumor volumes were measured weekly starting 20 days after tumor cell implantation. (n = 7–10 mice per group, a = p ≤ 0.05, b = p ≤ 0.09, 21% AL vs. all other groups; c = p < 0.008, 7% AL vs. 21% IF; d = p < 0.006, 7% AL vs 7% IF). Data in A-B for AL fed mice was previously published in part [7] and is shown here for comparison. C. Growth rates of tumors in mice on each indicated diet was calculated using the method of Laird and Ware [34] from tumor volumes measured 3–12 weeks after tumor implantation (n = 9–10 mice per group, p < 0.0001).
Figure 2
Figure 2. A protein restricted diet inhibits mTORC1 signaling in tumors
A. Tissue lysates from tumor xenografts were examined for phosphorylation of S6 S240/S244 and AKT S473 by western blotting. B. Quantification of S6 and AKT phosphorylation, normalized to total S6 or AKT protein, was performed using NIH ImageJ. C. Quantification of S6, normalized to β-TUBULIN, was performed using NIH Image J (n = 7–10 tumors per group, * = p < 0.05 t-test following ANOVA).
Figure 3
Figure 3. A protein restricted diet inhibits mTORC1 signaling in vivo
Tissue lysates from A. liver, B. muscle, C. heart and D. adipose tissue were examined for phosphorylation of S6 S240/S244 and AKT S473 by western blotting. Quantification of S6 and AKT phosphorylation, normalized to total S6 or AKT protein, was performed using NIH ImageJ (n = 6–7 samples per group, means with the same letter are not significantly different from each other (Tukey–Kramer test following ANOVA, p < 0.05)).
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