Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage.
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
Emiliano
E
Institute of General Pathology, Laboratory of Cell Signaling, Catholic University Medical School, Rome Italy.
Toietta
Gabriele
G
Mele
Marina
M
Labate
Valentina
V
Ranieri
Sofia Chiatamone
SC
Fusco
Salvatore
S
Tesori
Valentina
V
Antonini
Annalisa
A
Maulucci
Giuseppe
G
De Spirito
Marco
M
Galeotti
Tommaso
T
Pani
Giovambattista
G
D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000963:Antimetabolites / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D016895:Culture Media, Serum-Free; D003847:Deoxyglucose / Q000008:administration & dosage; D005508:Food Deprivation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D038601:Ribosomal Protein S6 / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism* / Q000633:toxicity
D000963:Antimetabolites; D016895:Culture Media, Serum-Free; D047908:Intracellular Signaling Peptides and Proteins; D038601:Ribosomal Protein S6; D003847:Deoxyglucose; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1