Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage

Emiliano Panieri, Gabriele Toietta, Marina Mele, Valentina Labate, Sofia Chiatamone Ranieri, Salvatore Fusco, Valentina Tesori, Annalisa Antonini, Giuseppe Maulucci, Marco De Spirito, Tommaso Galeotti, Giovambattista Pani

Research output: Contribution to journalArticlepeer-review

Abstract

Deregulated nutrient signaling plays pivotal roles in body ageing and in diabetic complications; biochemical cascades linking energy dysmetabolism to cell damage and loss are still incompletely clarified, and novel molecular paradigms and pharmacological targets critically needed. We provide evidence that in the retrovirus-packaging cell line HEK293-T Phoenix, massive cell death in serum-free medium is remarkably prevented or attenuated by either glucose or aminoacid withdrawal, and by the glycolysis inhibitor 2-deoxy-glucose. A similar protection was also elicited by interference with mitochondrial function, clearly suggesting involvement of energy metabolism in increased cell survival. Oxidative stress did not account for nutrient toxicity on serum-starved cells. Instead, nutrient restriction was associated with reduced activity of the mTOR/S6 Kinase cascade. Moreover, pharmacological and genetic manipulation of the mTOR pathway modulated in an opposite fashion signaling to S6K/S6 and cell viability in nutrient-repleted medium. Additionally, stimulation of the AMP-activated Protein Kinase concomitantly inhibited mTOR signaling and cell death, while neither event was affected by overexpression of the NAD+ dependent deacetylase Sirt-1, another cellular sensor of nutrient scarcity. Finally, blockade of the mTOR cascade reduced hyperglycemic damage also in a more pathophysiologically relevant model, i.e. in human umbilical vein endothelial cells (HUVEC) exposed to hyperglycemia. Taken together these findings point to a key role of the mTOR/S6K cascade in cell damage by excess nutrients and scarcity of growth-factors, a condition shared by diabetes and other ageing-related pathologies.

Original languageEnglish
Pages (from-to)487-503
Number of pages17
JournalAging
Volume2
Issue number8
Publication statusPublished - Aug 2010

Keywords

  • Ageing
  • Cell death
  • Endothelial cells
  • Growth factor withdrawal
  • mTOR
  • Nutrients

ASJC Scopus subject areas

  • Ageing
  • Cell Biology
  • Geriatrics and Gerontology

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