Sorafenib, a multikinase inhibitor, induces formation of stress granules in hepatocarcinoma cells

// Pauline Adjibade 1, 2, 3 , Valerie Grenier St-Sauveur 1, 2, 3 , Miguel Quevillon Huberdeau 1, 2, 3 , Marie-Josee Fournier 1, 2, 3 , Andreanne Savard 1, 2, 3 , Laetitia Coudert 1, 2, 3 , Edouard W. Khandjian 4, 5 , Rachid Mazroui 1, 2, 3 1 Centre de Recherche du toCHU de Quebec, Universite Laval, Quebec, PQ, Canada 2 Departement de Biologie Moleculaire, Biochimie Medicale et Pathologie, Faculte de Medecine, Universite Laval, Quebec, PQ, Canada 3 Centre de Recherche en Cancerologie de l’Universite Laval, Universite Laval, Quebec, PQ, Canada 4 Centre de Recherche, Institut Universitaire en Sante Mentale de Quebec, Universite Laval, Quebec, PQ, Canada 5 Departement de Psychiatrie et de Neurosciences, Faculte de Medecine, Universite Laval, Quebec, PQ, Canada Correspondence to: Rachid Mazroui, e-mail: rachid.mazroui@crsfa.ulaval.ca Keywords: stress granules, sorafenib, PERK, eIF2a, ATF4 Received: July 13, 2015      Accepted: October 04, 2015      Published: November 02, 2015 ABSTRACT Stress granules (SGs) are cytoplasmic RNA multimeric bodies that form under stress conditions known to inhibit translation initiation. In most reported stress cases, the formation of SGs was associated with the cell recovery from stress and survival. In cells derived from cancer, SGs formation was shown to promote resistance to either proteasome inhibitors or 5-Fluorouracil used as chemotherapeutic agents. Despite these studies, the induction of SGs by chemotherapeutic drugs contributing to cancer cells resistance is still understudied. Here we identified sorafenib, a tyrosine kinase inhibitor used to treat hepatocarcinoma, as a potent chemotherapeutic inducer of SGs. The formation of SGs in sorafenib-treated hepatocarcionoma cells correlates with inhibition of translation initiation; both events requiring the phosphorylation of the translation initiation factor eIF2α. Further characterisation of the mechanism of sorafenib-induced SGs revealed PERK as the main eIF2α kinase responsible for SGs formation. Depletion experiments support the implication of PERK-eIF2α-SGs pathway in hepatocarcinoma cells resistance to sorafenib. This study also suggests the existence of an unexpected complex regulatory balance between SGs and phospho-eIF2α where SGs dampen the activation of the phospho-eIF2α-downstream ATF4 cell death pathway.