Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma

doi:10.3390/ijms22083934

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/23647

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/23647

Title:	Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma
Authors:	Chang, CY;Pan, PH;Wu, CC;Liao, SL;Chen, WY;Kuan, YH;Wang, WY;Chen, CJ
Keywords:	apoptosis;EGFR inhibitors;ER stress;glioma;Noxa
Date:	2021
Issue Date:	2022-08-05T09:40:39Z (UTC)
Publisher:	MDPI
Abstract:	Adequate stress on the Endoplasmic Reticulum (ER) with the Unfolded Protein Response (UPR) could maintain glioma malignancy. Uncontrolled ER stress, on the other hand, predisposes an apoptosis-dominant UPR program. We studied here the proapoptotic actions of the Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib, with the focus on ER stress. The study models were human H4 and U87 glioma cell lines. We found that the glioma cell-killing effects of gefitinib involved caspase 3 apoptotic cascades. Three branches of ER stress, namely Activating Transcription Factor-6 (ATF6), Protein Kinase R (PKR)-Like ER Kinase (PERK), and Inositol-Requiring Enzyme 1 (IRE1), were activated by gefitinib, along with the elevation of intracellular free Ca2+, Reactive Oxygen Species (ROS), and NADPH Oxidase2/4 (NOX2/4). Specifically, elevated IRE1 phosphorylation, Tumor Necrosis Factor (TNF) Receptor-Associated Factor-2 (TRAF2) expression, Apoptosis Signal-Regulating Kinase-1 (Ask1) phosphorylation, c-Jun N-Terminal Kinase (JNK) phosphorylation, and Noxa expression appeared in gefitinib-treated glioma cells. Genetic, pharmacological, and biochemical studies further indicated an active ROS/ER stress/Ask1/JNK/Noxa axis causing the glioma apoptosis induced by gefitinib. The findings suggest that ER-stress-based therapeutic targeting could be a promising option in EGFR inhibitor glioma therapy, and may ultimately achieve a better patient response.
URI:	http://dx.doi.org/10.3390/ijms22083934 https://www.webofscience.com/wos/woscc/full-record/WOS:000644320100001 https://ir.csmu.edu.tw:8080/handle/310902500/23647
Relation:	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES ,2021,v22,issue 8
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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