PKR and GCN2 stress kinases promote an ER stress-independent eIF2α phosphorylation responsible for calreticulin exposure in melanoma cells

Oncoimmunology
Paola GiglioMarco Corazzari

Abstract

The immunogenic cell death (ICD) process represents a novel therapeutic approach to treat tumours, in which cytotoxic compounds promote both cancer cell death and the emission of damage-associated molecular patterns (DAMPs) from dying cells, to activate the immune system against the malignancy. Therefore, we explored the possibility to stimulate the key molecular players with a pivotal role in the execution of the ICD program in melanoma cells. To this aim, we used the pro-ICD agents mitoxantrone and doxorubicin and found that both agents could induce cell death and stimulate the release/exposure of the strictly required DAMPs in melanoma cells: i) calreticulin (CRT) exposure on the cell membrane; ii) ATP secretion; iii) type I IFNs gene up-regulation and iv) HMGB1 secretion, highlighting no interference by oncogenic BRAF. Importantly, although the ER stress-related PERK activation has been linked to CRT externalization, through the phosphorylation of eIF2α, we found that this stress pathway together with PERK were not involved in melanoma cells. Notably, we identified PKR and GCN2 as key mediators of eIF2α phosphorylation, facilitating the translocation of CTR on melanoma cells surface, under pro-ICD drugs stimulation. Therefo...Continue Reading

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Citations

Oct 28, 2019·Oncoimmunology·Jenny SprootenAbhishek D Garg
Apr 24, 2020·EMBO Molecular Medicine·Juliette HumeauGuido Kroemer
Mar 30, 2020·Journal for Immunotherapy of Cancer·Yan WangGuido Kroemer
Jul 8, 2020·Critical Reviews in Biochemistry and Molecular Biology·Xiaodan QinHui Feng
Aug 21, 2020·Cell Cycle·Mara GagliardiMarco Corazzari
Apr 8, 2019·Archives of Pharmacal Research·Marc Diederich
Feb 1, 2020·Oncoimmunology·Isaure VanmeerbeekAbhishek D Garg
Jan 31, 2020·Frontiers in Oncology·Luca Di LeoDaniela De Zio
Jul 28, 2020·Cellular Oncology (Dordrecht)·Changlin LiBenyi Li
Nov 30, 2019·Cell Death & Disease·Mara GagliardiMarco Corazzari
Nov 28, 2020·Cell Death & Disease·Jitka FucikovaLorenzo Galluzzi
Nov 5, 2020·Antioxidants & Redox Signaling·Congying PuMin Huang
Apr 23, 2021·Macromolecular Bioscience·Liwen FuChuanglong He

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Methods Mentioned

BETA
confocal microscopy
flow cytometry
transfection
electrophoresis
PCR
Assay
ELISA

Software Mentioned

GraphPad Prism
Image Lab
IDT PrimerQuest Tool

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