title: Cell survival under nutrient stress is dependent on metabolic conditions regulated by Akt and not by autophagic vacuoles.
abstract: Akt activation assists tumor cell survival and promotes resistance to chemotherapy. Here we show that constitutively active Akt (CA-Akt) cells are highly sensitized to cell death induced by nutrient and growth factor deprivation, whereas dominant-negative Akt (DN-Akt) cells have a high rate of survival. The content of autophagosomes in starved CA-Akt cells was high, while DN-Akt cells expressed autophagic vacuoles constitutively, independently of nutrition conditions. Thus Akt down-regulation and downstream events can induce autophagosomes which were not directly determinants of cell death. Biochemical analysis in Akt-mutated cells show that (i) Akt and mTOR proteins were degraded more rapidly than the housekeeping proteins, (ii) mTOR phosphorylation at position Thr(2446) was relatively high in DN-Akt and low in CA-Akt cells, induced by starvation in mock cells only, which suggests reduced autoregulation of these pathways in Akt-mutated cells, (iii) both protein synthesis and protein degradation were significantly higher in starved CA-Akt cells than in starved DN-Akt cells or mock cells. In conclusion, constitutively active Akt, unable to control synthesis and wasting of proteins, accelerates the death of starved cells.
authors.affiliation: Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bruno
authors.forename: A
authors.initials: A
authors.lastname: Calastretti
authors.forename: M
authors.initials: M
authors.lastname: Priulla
authors.forename: L
authors.initials: L
authors.lastname: Asnaghi
authors.forename: F
authors.initials: F
authors.lastname: Scarlatti
authors.forename: A
authors.initials: A
authors.lastname: Nicolin
authors.forename: G
authors.initials: G
authors.lastname: Canti
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D002460:Cell Line; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D006801:Humans; D009154:Mutation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014617:Vacuoles / Q000378:metabolism
chemical_list: D016895:Culture Media, Serum-Free; D011506:Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases