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

Dudley W. Lamming, Nicole E. Cummings, Antonella L. Rastelli, Feng Gao, Edda Cava, Beatrice Bertozzi, Francesco Spelta, Roberto Pili, Luigi Fontana

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)31233-31240
Number of pages8
JournalOncotarget
Volume6
Issue number31
DOIs
StatePublished - 2015

Fingerprint

Dietary Proteins
Heterografts
Fasting
Neoplasms
Proteins
Sirolimus
Growth
TOR Serine-Threonine Kinases
Phosphorylation
S 6
Amino Acids
Protein Kinases
Rodentia
Down-Regulation
Cell Culture Techniques
Breast Neoplasms

Keywords

  • Aging
  • Cancer
  • Mice
  • MTOR
  • Protein restriction

ASJC Scopus subject areas

  • Oncology

Cite this

Lamming, D. W., Cummings, N. E., Rastelli, A. L., Gao, F., Cava, E., Bertozzi, B., ... Fontana, L. (2015). Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model. Oncotarget, 6(31), 31233-31240. https://doi.org/10.18632/oncotarget.5180

Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model. / Lamming, Dudley W.; Cummings, Nicole E.; Rastelli, Antonella L.; Gao, Feng; Cava, Edda; Bertozzi, Beatrice; Spelta, Francesco; Pili, Roberto; Fontana, Luigi.

In: Oncotarget, Vol. 6, No. 31, 2015, p. 31233-31240.

Research output: Contribution to journalArticle

Lamming, DW, Cummings, NE, Rastelli, AL, Gao, F, Cava, E, Bertozzi, B, Spelta, F, Pili, R & Fontana, L 2015, 'Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model', Oncotarget, vol. 6, no. 31, pp. 31233-31240. https://doi.org/10.18632/oncotarget.5180
Lamming, Dudley W. ; Cummings, Nicole E. ; Rastelli, Antonella L. ; Gao, Feng ; Cava, Edda ; Bertozzi, Beatrice ; Spelta, Francesco ; Pili, Roberto ; Fontana, Luigi. / Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model. In: Oncotarget. 2015 ; Vol. 6, No. 31. pp. 31233-31240.
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