title: Sorafenib, a multikinase inhibitor, induces formation of stress granules in hepatocarcinoma cells.
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.
authors.affiliation: Centre de Recherche du toCHU de Québec, Université Laval, Québec, PQ, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, PQ, Canada.|Centre de Recherche en Cancérologie de l'Université Laval, Université Laval, Québec, PQ, Canada.
authors.forename: Pauline
authors.initials: P
authors.lastname: Adjibade
authors.affiliation: Centre de Recherche du toCHU de Québec, Université Laval, Québec, PQ, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, PQ, Canada.|Centre de Recherche en Cancérologie de l'Université Laval, Université Laval, Québec, PQ, Canada.
authors.forename: Valérie Grenier
authors.initials: VG
authors.lastname: St-Sauveur
authors.affiliation: Centre de Recherche du toCHU de Québec, Université Laval, Québec, PQ, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, PQ, Canada.|Centre de Recherche en Cancérologie de l'Université Laval, Université Laval, Québec, PQ, Canada.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quevillon Huberdeau
authors.affiliation: Centre de Recherche du toCHU de Québec, Université Laval, Québec, PQ, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, PQ, Canada.|Centre de Recherche en Cancérologie de l'Université Laval, Université Laval, Québec, PQ, Canada.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Fournier
authors.affiliation: Centre de Recherche du toCHU de Québec, Université Laval, Québec, PQ, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, PQ, Canada.|Centre de Recherche en Cancérologie de l'Université Laval, Université Laval, Québec, PQ, Canada.
authors.forename: Andreanne
authors.initials: A
authors.lastname: Savard
authors.affiliation: Centre de Recherche du toCHU de Québec, Université Laval, Québec, PQ, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, PQ, Canada.|Centre de Recherche en Cancérologie de l'Université Laval, Université Laval, Québec, PQ, Canada.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Coudert
authors.affiliation: Centre de Recherche, Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec, PQ, Canada.|Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, PQ, Canada.
authors.forename: Edouard W
authors.initials: EW
authors.lastname: Khandjian
authors.affiliation: Centre de Recherche du toCHU de Québec, Université Laval, Québec, PQ, Canada.|Département de Biologie Moléculaire, Biochimie Médicale et Pathologie, Faculté de Médecine, Université Laval, Québec, PQ, Canada.|Centre de Recherche en Cancérologie de l'Université Laval, Université Laval, Québec, PQ, Canada.
authors.forename: Rachid
authors.initials: R
authors.lastname: Mazroui
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib; D013312:Stress, Physiological / Q000502:physiology; D014162:Transfection
chemical_list: C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; D009536:Niacinamide; D000077157:Sorafenib
keywords: ATF4; PERK; eIF2a; sorafenib; stress granules