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

被引:67
作者
Adjibade, Pauline [1 ,2 ,3 ]
St-Sauveur, Valerie Grenier [1 ,2 ,3 ]
Huberdeau, Miguel Quevillon [1 ,2 ,3 ]
Fournier, Marie-Josee [1 ,2 ,3 ]
Savard, Andreanne [1 ,2 ,3 ]
Coudert, Laetitia [1 ,2 ,3 ]
Khandjian, Edouard W. [4 ,5 ]
Mazroui, Rachid [1 ,2 ,3 ]
机构
[1] Univ Laval, CHU Quebec, Ctr Rech, Quebec City, PQ, Canada
[2] Univ Laval, Fac Med, Dept Biol Mol Biochim Med & Pathol, Quebec City, PQ G1K 7P4, Canada
[3] Univ Laval, Ctr Rech Cancerol, Quebec City, PQ, Canada
[4] Univ Laval, Ctr Rech, Inst Univ Sante Mentale Quebec, Quebec City, PQ, Canada
[5] Univ Laval, Fac Med, Dept Psychiat & Neurosci, Quebec City, PQ G1K 7P4, Canada
关键词
stress granules; sorafenib; PERK; eIF2a; ATF4; UNFOLDED-PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM KINASE; HEPATOCELLULAR-CARCINOMA; TRANSLATION INITIATION; ER-STRESS; EIF2-ALPHA KINASES; VIRAL-INFECTION; GENE-EXPRESSION; MESSENGER-RNAS; IN-VITRO;
D O I
10.18632/oncotarget.5980
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 eIF2'. Further characterisation of the mechanism of sorafenib-induced SGs revealed PERK as the main eIF2' kinase responsible for SGs formation. Depletion experiments support the implication of PERK-eIF2'-SGs pathway in hepatocarcinoma cells resistance to sorafenib. This study also suggests the existence of an unexpected complex regulatory balance between SGs and phospho-eIF2' where SGs dampen the activation of the phospho-eIF2'-downstream ATF4 cell death pathway.
引用
收藏
页码:43927 / 43943
页数:17
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