title: Glucose regulates protein catabolism in ras-transformed fibroblasts through a lysosomal-dependent proteolytic pathway.
abstract: Transformed cells are exposed to heterogeneous microenvironments, including low D-glucose (Glc) concentrations inside tumours. The regulation of protein turnover is commonly impaired in many types of transformed cells, but the role of Glc in this regulation is unknown. In the present study we demonstrate that Glc controls protein turnover in ras-transformed fibroblasts (KBALB). The regulation by Glc of protein breakdown was correlated with modifications in the levels of lysosomal cathepsins B, L and D, while autophagic sequestration and non-lysosomal proteolytic systems (m- and mu-calpains and the zeta-subunit of the proteasome) remained unaffected. Lactacystin, a selective inhibitor of the proteasome, depressed proteolysis, but did not prevent its regulation by Glc. The sole inhibition of the cysteine endopeptidases (cathepsins B and L, and calpains) by E-64d [(2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester] was also not sufficient to alter the effect of Glc on proteolysis. The Glc-dependent increase in proteolysis was, however, prevented after optimal inhibition of lysosomal cysteine and aspartic endopeptidases by methylamine. We conclude that, in transformed cells, Glc plays a critical role in the regulation of protein turnover and that the lysosomal proteolytic capacity is mainly responsible for the control of intracellular proteolysis by Glc.
authors: UR 238, Unité de Nutrition Cellulaire et Moléculaire, Centre de Recherche en Nutrition Humaine, Institut National de la Recherche Agronomique, 63122 St Genès Champanelle, France.
authors: C
authors: C
authors: Tournu
authors: A
authors: A
authors: Obled
authors: M P
authors: MP
authors: Roux
authors: M
authors: M
authors: Ferrara
authors: S
authors: S
authors: Omura
authors: D M
authors: DM
authors: Béchet
mesh_terms: D016475:3T3 Cells; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D010450:Endopeptidases; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011905:Genes, ras; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007708:Kirsten murine sarcoma virus / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D008715:Methionine / Q000378:metabolism; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D015853:Cysteine Proteinase Inhibitors; D008744:Methylamines; D011506:Proteins; C067713:lactacystin; D008715:Methionine; C027451:methylamine; D007770:L-Lactate Dehydrogenase; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D002402:Cathepsin D; D005947:Glucose; D000111:Acetylcysteine