The prohibitin-binding compound fluorizoline affects multiple components of the translational machinery and inhibits protein synthesis.
Fiche publication
Date publication
mai 2020
Journal
The Journal of biological chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent
Tous les auteurs :
Jin X, Xie J, Zabolocki M, Wang X, Jiang T, Wang D, Desaubry L, Bardy C, Proud CG
Lien Pubmed
Résumé
Fluorizoline (FLZ) binds to prohibitin-1 and -2 (PHB1/2), which are pleiotropic scaffold proteins known to affect signaling pathways involved in several intracellular processes. However, it is not yet clear how FLZ exerts its effect. Here, we show that exposure of three different human cancer cell lines to FLZ increases the phosphorylation of key translation factors, particularly of initiation factor 2 (eIF2) and elongation factor 2 (eEF2), modifications that inhibit their activities. FLZ also impaired signaling through mTOR complex 1, which also regulates the translational machinery, e.g. through the eIF4E-binding protein 4E-BP1. In line with these findings, FLZ potently inhibited protein synthesis. We noted that the first phase of this inhibition involves very rapid eEF2 phosphorylation, which is catalyzed by a dedicated Ca-dependent protein kinase, eEF2 kinase (eEF2K). We also demonstrate that FLZ induces a swift and marked rise in intracellular Ca levels, likely explaining the effects on eEF2. Disruption of normal Ca homeostasis can also induce endoplasmic reticulum stress, and our results suggest that induction of this stress response contributes to the increased phosphorylation of eIF2, likely due to activation of the eIF2-modifying kinase PKR-like endoplasmic reticulum kinase (PERK). We show that FLZ induces cancer cell death and that this effect involves contributions from the phosphorylation of both eEF2 and eIF2. Our findings provide important new insights into the biological effects of FLZ and thus the roles of PHBs, specifically in regulating Ca levels, cellular protein synthesis, and cell survival.
Mots clés
calcium, cancer, cell death, eEF2, endoplasmic reticulum stress (ER stress), eukaryotic initiation factor 2 (eIF2), eukaryotic translation initiation, prohibitin, protein synthesis, translation elongation factor
Référence
J. Biol. Chem.. 2020 May 19;: