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  MetAP1 and MetAP2 drive cell selectivity for a potent anti-cancer agent in synergy, by controlling glutathione redox state

Frottin, F., Bienvenut, W. V., Bignon, J., Jacquet, E., Jacome, A. S. V., Van Dorsselaer, A., et al. (2016). MetAP1 and MetAP2 drive cell selectivity for a potent anti-cancer agent in synergy, by controlling glutathione redox state. Oncotarget, 7(39), 63306-63323. doi:10.18632/oncotarget.11216.

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 Creators:
Frottin, Frederic1, Author              
Bienvenut, Willy V.2, Author
Bignon, Jerome2, Author
Jacquet, Eric2, Author
Jacome, Alvaro Sebastian Vaca2, Author
Van Dorsselaer, Alain2, Author
Cianferani, Sarah2, Author
Carapito, Christine2, Author
Meinnel, Thierry2, Author
Giglione, Carmela2, Author
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_persistent22              
2external, ou_persistent22              

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Free keywords: TERMINAL METHIONINE EXCISION; END RULE PATHWAY; CANCER-CELLS; ENDOTHELIAL-CELLS; ESCHERICHIA-COLI; GROWTH ARREST; AMINOPEPTIDASE-2; FUMAGILLIN; TNP-470; INHIBITIONOncology; Cell Biology; cotranslational modifications; quantitative targeted proteomics; methionine aminopeptidase; N-terminal processing; glutathione redox homeostasis;
 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.

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Language(s): eng - English
 Dates: 2016-08-112016
 Publication Status: Published in print
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000387167800038
DOI: 10.18632/oncotarget.11216
 Degree: -

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Title: Oncotarget
Source Genre: Journal
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Publ. Info: 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA : IMPACT JOURNALS LLC
Pages: - Volume / Issue: 7 (39) Sequence Number: - Start / End Page: 63306 - 63323 Identifier: ISSN: 1949-2553