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.

Panieri, E., Toietta, G., Mele, M., Labate, V., Chiatamone Ranieri, S., Fusco, S., Tesori, V., Antonini, A., Maulucci, G., De Spirito, M., Galeotti, T., Pani, G., Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage., <<AGING>>, 2010; 2 (Agosto): 487-503.. [doi:10.18632/aging.100183] [http://hdl.handle.net/10807/3885]

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

Panieri, Emiliano;Mele, Marina;Labate, Valentina;Chiatamone Ranieri, Sofia;Fusco, Salvatore;Tesori, Valentina;Maulucci, Giuseppe;De Spirito, Marco;Galeotti, Tommaso;Pani, Giovambattista
2010

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.
2010
Inglese
Panieri, E., Toietta, G., Mele, M., Labate, V., Chiatamone Ranieri, S., Fusco, S., Tesori, V., Antonini, A., Maulucci, G., De Spirito, M., Galeotti, T., Pani, G., Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage., <<AGING>>, 2010; 2 (Agosto): 487-503.. [doi:10.18632/aging.100183] [http://hdl.handle.net/10807/3885]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/3885
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