Journal
ONCOTARGET
Volume 6, Issue 41, Pages 43927-43943Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5980
Keywords
stress granules; sorafenib; PERK; eIF2a; ATF4
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Funding
- Louis Poirier scholarship (Fondation du CHU de Quebec)
- Canadian Institute Health Research (CH-IR) [MOP-IC093226-CBT]
- Canadian Foundation for Innovation [MOP-GF091050]
- Canadian Cancer Society Research Institute (Innovation) [702406]
- CIHR
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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.
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