title: MetAP1 and MetAP2 drive cell selectivity for a potent anti-cancer agent in synergy, by controlling glutathione redox state.
abstract: Fumagillin and its derivatives are therapeutically useful because they can decrease cancer progression. The specific molecular target of fumagillin is methionine aminopeptidase 2 (MetAP2), one of the two MetAPs present in the cytosol. MetAPs catalyze N-terminal methionine excision (NME), an essential pathway of cotranslational protein maturation. To date, it remains unclear the respective contribution of MetAP1 and MetAP2 to the NME process in vivo and why MetAP2 inhibition causes cell cycle arrest only in a subset of cells. Here, we performed a global characterization of the N-terminal methionine excision pathway and the inhibition of MetAP2 by fumagillin in a number of lines, including cancer cell lines. Large-scale N-terminus profiling in cells responsive and unresponsive to fumagillin treatment revealed that both MetAPs were required in vivo for M[VT]X-targets and, possibly, for lower-level M[G]X-targets. Interestingly, we found that the responsiveness of the cell lines to fumagillin was correlated with the ability of the cells to modulate their glutathione homeostasis. Indeed, alterations to glutathione status were observed in fumagillin-sensitive cells but not in cells unresponsive to this agent. Proteo-transcriptomic analyses revealed that both MetAP1 and MetAP2 accumulated in a cell-specific manner and that cell sensitivity to fumagillin was related to the levels of these MetAPs, particularly MetAP1. We suggest that MetAP1 levels could be routinely checked in several types of tumor and used as a prognostic marker for predicting the response to treatments inhibiting MetAP2.
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, France.|Present address: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frottin
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, France.
authors.forename: Willy V
authors.initials: WV
authors.lastname: Bienvenut
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301, CNRS, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bignon
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301, CNRS, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Jacquet
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS, UMR7178, Strasbourg, France.
authors.forename: Alvaro Sebastian
authors.initials: AS
authors.lastname: Vaca Jacome
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS, UMR7178, Strasbourg, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS, UMR7178, Strasbourg, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cianferani
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS, UMR7178, Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Carapito
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Meinnel
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, France.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giglione
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D003510:Cyclohexanes / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000737:chemistry*; D006023:Glycoproteins / Q000378:metabolism*; D006706:Homeostasis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D063208:Methionyl Aminopeptidases; D010084:Oxidation-Reduction; D010641:Phenotype; D000072417:Protein Domains; D040901:Proteomics; D012717:Sesquiterpenes / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D006023:Glycoproteins; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C506619:METAP1 protein, human; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases; D005978:Glutathione
keywords: N-terminal processing; cotranslational modifications; glutathione redox homeostasis; methionine aminopeptidase; quantitative targeted proteomics