Rôle de l’<i>heme regulated inhibitor</i>(HRI) dans la résistance à l’apoptose

Joncas, France‐Hélène; Adjibade, Pauline; Mazrouï, Rachid

doi:10.1051/medsci/20143010015

Cited by 3 publications

(3 citation statements)

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“…5A–5B ), confirming previous studies [ 59 ]. Relative resistance to sorafenib-mediated apoptosis of SGs-forming Hep3B as compared to SGs-deficient Huh-7 is consistent with the well-established antiapoptotic role of SGs [ 60 ]. Massive apoptosis induction in SGs-deficient Huh-7 (Fig.…”

Section: Discussionsupporting

confidence: 69%

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

et al. 2015

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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 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.

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Section: Discussionsupporting

confidence: 69%

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

et al. 2015

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“…GCN2 (general control nonderepressible 2) phosphorylates eIF2α during amino acid deprivation [8] and PKR (Protein kinase R) is responsible for eIF2α phosphorylation during viral infection [9]. While HRI (heme-regulated inhibitor kinase) is activated and phosphorylates eIF2α in response to oxidative stress, heme deficiency, and proteasome inhibition [10], PERK (PKR-like endoplasmic reticulum kinase) phosphorylates eIF2α during endoplasmic reticulum stress [7,11]. Once phosphorylated, eIF2α induces stalling of translation initiation complexes in an inactive form whose accumulation results on SG formation [12].…”

Section: Introductionmentioning

confidence: 99%

Treatment of cancer cells with Lapatinib negatively regulates general translation and induces stress granules formation

et al. 2020

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Stress granules (SG) are cytoplasmic RNA granules that form during various types of stress known to inhibit general translation, including oxidative stress, hypoxia, endoplasmic reticulum stress (ER), ionizing radiations or viral infection. Induction of these SG promotes cell survival in part through sequestration of proapoptotic molecules, resulting in the inactivation of cell death pathways. SG also form in cancer cells, but studies investigating their formation upon treatment with chemotherapeutics are very limited. Here we identified Lapatinib (Tykerb / Tyverb ®), a tyrosine kinase inhibitor used for the treatment of breast cancers as a new inducer of SG in breast cancer cells. Lapatinib-induced SG formation correlates with the inhibition of general translation initiation which involves the phosphorylation of the translation initiation factor eIF2α through the kinase PERK. Disrupting PERK-SG formation by PERK depletion experiments sensitizes resistant breast cancer cells to Lapatinib. This study further supports the assumption that treatment with anticancer drugs activates the SG pathway, which may constitute an intrinsic stress response used by cancer cells to resist treatment.

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“…Ces kinases peuvent être activées séparément ou simultanément, selon les stress auxquels la cellule est exposée [3]. Au nombre de quatre, elles ont été décrites en détail dans un précédent article de m/s[30] (➜). L'autre voie d'inhibition de la traduction, activée par la réponse au stress, fait intervenir une altération des fonctions du complexe EIF4F, composé des protéines EIF4E-EIF4G-EIF4A[31].…”

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Les granules de stress, des acteurs émergents en cancérologie

2021

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Les stress induits au sein des tumeurs en cours de développement (hypoxie, stress oxydant, etc.) sont connus depuis de nombreuses années. Cependant, l’implication de la réponse au stress dans le processus tumoral est un concept récent. Les granules de stress (GS) sont des structures cytoplasmiques qui se forment à la suite d’une exposition à un stress et qui ont des effets cytoprotecteurs. De nombreuses données sont en faveur de l’implication de ces granules dans l’évolution tumorale et métastatique, mais aussi dans le développement de la chimiorésistance des tumeurs. Nous abordons dans cet article le rôle particulier des granules de stress en cancérologie et, plus spécifiquement, celui des protéines qui contrôlent leur formation.

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Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

Cited by 3 publications

References 51 publications

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

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

Treatment of cancer cells with Lapatinib negatively regulates general translation and induces stress granules formation

Les granules de stress, des acteurs émergents en cancérologie

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