MetAP1 and MetAP2 drive cell selectivity for a potent anti-cancer agent in synergy, by controlling glutathione redox state
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Frédéric Frottin1,4, Willy V. Bienvenut1, Jérôme Bignon2, Eric Jacquet2, Alvaro Sebastian Vaca Jacome3, Alain Van Dorsselaer3, Sarah Cianferani3, Christine Carapito3, Thierry Meinnel1, Carmela Giglione1
1Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France
2Institut de Chimie des Substances Naturelles, UPR2301, CNRS avenue de la terrasse, Gif sur Yvette Cedex, France
3Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS, UMR7178, 67087 Strasbourg, France
4Present address: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82159 Martinsried, Germany
Carmela Giglione, email: [email protected]
Keywords: cotranslational modifications, quantitative targeted proteomics, methionine aminopeptidase, N-terminal processing, glutathione redox homeostasis
Received: May 10, 2016 Accepted: July 19, 2016 Published: August 11, 2016
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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