RSL3, a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating GPx4. Here we report the purification of the protein indispensable for GPx4 inactivation by RSL3. MS analysis reveals 14-3-3 isoforms as candidates and recombinant human 14-3-3epsilon confirms the identification. The function of 14-3-3 is redox-regulated. Moreover, overexpression and silencing of the gene coding for 14-3-3 consistently control the inactivation of GPx4 by RSL3. The interaction of GPx4 with a redox-regulated adaptor protein, operating in cell signalling, further contributes to frame it within redox-regulated pathways of cell survival and death and opens new therapeutic perspectives.

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis-inducing molecule RSL3 requires the adaptor protein 14-3-3 epsilon

Ana-Marija Vučković;Valentina Bosello Travain;Luciana Bordin;Giorgio Cozza;Giovanni Miotto;Monica Rossetto;Stefano Toppo;Rina Venerando;Mattia Zaccarin;Matilde Maiorino;Fulvio Ursini;Antonella Roveri
2019

Abstract

RSL3, a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating GPx4. Here we report the purification of the protein indispensable for GPx4 inactivation by RSL3. MS analysis reveals 14-3-3 isoforms as candidates and recombinant human 14-3-3epsilon confirms the identification. The function of 14-3-3 is redox-regulated. Moreover, overexpression and silencing of the gene coding for 14-3-3 consistently control the inactivation of GPx4 by RSL3. The interaction of GPx4 with a redox-regulated adaptor protein, operating in cell signalling, further contributes to frame it within redox-regulated pathways of cell survival and death and opens new therapeutic perspectives.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3310112
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