IRE1α deficiency promotes tumor cell death and eIF2α degradation through PERK dipendent autophagy

Antonello Storniolo, Vincenzo Alfano, Sabino Carbotta, Elisabetta Ferretti, Livia Di Renzo

Research output: Contribution to journalArticle

Abstract

Sensors of endoplasmic reticulum (ER) stress function in a co-ordinated manner. In the present study we investigated the relationship between IRE1α and PERK pathways and survival of ER stressed U937 cells and BC3 cells. To this end, we investigated the effects of a subcytotoxic concentration of Tunicamycin in IRE1α-proficient and in IRE1α-deficient cells, by pharmacological inhibition with 4μ8 C or down-regulation by specific siRNA. We show that either type of IRE1α deficiency affects eIF2α expression and causes cell death increase. GSK2606414, a PERK inhibitor, and PERK specific siRNA prevent eIF2α down-regulation and restore cell survival. Degradation of this protein is due to autophagy, as it is prevented by bafilomycin and not by proteasome inhibition. Furthermore, activation of the autophagy flux is PERK dependent. Also the Cathepsin B inhibitor CA074 prevents eIF2α from degradation and reduces cell death. Altogether, these results show that IRE1α deficiency in ER stressed cells leads to an unexpected decrease of eIF2α, an important molecule for protein translation, through PERK dependent autophagy. Thus, IRE1/XBP1 inhibitors may represent a feasible strategy for tumor therapy, while PERK inhibitors may vanish the goal.

Original languageEnglish
Pages (from-to)3
JournalCell Death Discovery
Volume4
DOIs
Publication statusPublished - Jan 29 2018

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Autophagy
Cell Death
Endoplasmic Reticulum
Small Interfering RNA
Down-Regulation
Tunicamycin
Neoplasms
Cathepsin B
U937 Cells
Endoplasmic Reticulum Stress
Protein Biosynthesis
Proteasome Endopeptidase Complex
Proteolysis
Cause of Death
Cell Survival
Pharmacology
Therapeutics

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IRE1α deficiency promotes tumor cell death and eIF2α degradation through PERK dipendent autophagy. / Storniolo, Antonello; Alfano, Vincenzo; Carbotta, Sabino; Ferretti, Elisabetta; Di Renzo, Livia.

In: Cell Death Discovery, Vol. 4, 29.01.2018, p. 3.

Research output: Contribution to journalArticle

Storniolo, Antonello ; Alfano, Vincenzo ; Carbotta, Sabino ; Ferretti, Elisabetta ; Di Renzo, Livia. / IRE1α deficiency promotes tumor cell death and eIF2α degradation through PERK dipendent autophagy. In: Cell Death Discovery. 2018 ; Vol. 4. pp. 3.
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