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.
- cell death