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Open AccessArticle

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

1
Department of Surgery, Feng Yuan Hospital, Taichung City 420, Taiwan
2
Division of Urology, Taichung Veterans General Hospital, Taichung City 407, Taiwan
3
Department of Anesthesiology, Taichung Veterans General Hospital, Taichung City 407, Taiwan
4
Department of Financial Engineering, Providence University, Taichung City 433, Taiwan
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Department of Data Science and Big Data Analytics, Providence University, Taichung City 433, Taiwan
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Children’s Medical Center, Taichung Veterans General Hospital, Taichung City 407, Taiwan
7
Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung City 407, Taiwan
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Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan
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Department of Veterinary Medicine, National Chung Hsing University, Taichung City 402, Taiwan
10
Department of Nursing, HungKuang University, Taichung City 433, Taiwan
11
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City 404, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(2), 557; https://doi.org/10.3390/ijms21020557
Received: 10 December 2019 / Revised: 7 January 2020 / Accepted: 14 January 2020 / Published: 15 January 2020
(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)
The dormancy of cellular apoptotic machinery has been highlighted as a crucial factor in therapeutic resistance, recurrence, and poor prognosis in patients with malignancy, such as malignant glioma. Increasing evidence indicates that nonsteroidal anti-inflammatory drugs (NSAIDs) confer chemopreventive effects, and indomethacin has been shown to have a novel chemotherapeutic application targeting glioma cells. To extend these findings, herein, we studied the underlying mechanisms of apoptosis activation caused by indomethacin in human H4 and U87 glioma cells. We found that the glioma cell-killing effects of indomethacin involved both death receptor- and mitochondria-mediated apoptotic cascades. Indomethacin-induced glioma cell apoptosis was accompanied by a series of biochemical changes, including reactive oxygen species generation, endoplasmic reticulum (ER) stress, apoptosis signal-regulating kinase-1 (Ask1) activation, p38 hyperphosphorylation, protein phosphatase 2A (PP2A) activation, Akt dephosphorylation, Mcl-1 and FLICE-inhibiting protein (FLIP) downregulation, Bax mitochondrial distribution, and caspases 3/caspase 8/caspase 9 activation. Data on pharmacological inhibition related to oxidative stress, ER stress, free Ca2+, and p38 revealed that the axis of oxidative stress/ER stress/Ask1/p38/PP2A/Akt comprised an apoptotic cascade leading to Mcl-1/FLIP downregulation and glioma apoptosis. Since indomethacin is an emerging choice in chemotherapy and its antineoplastic effects have been demonstrated in glioma tumor-bearing models, the findings further strengthen the argument for turning on the aforementioned axis in order to activate the apoptotic machinery of glioma cells. View Full-Text
Keywords: apoptosis; ER stress; glioma; NSAID apoptosis; ER stress; glioma; NSAID
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Chang, C.-Y.; Li, J.-R.; Wu, C.-C.; Wang, J.-D.; Liao, S.-L.; Chen, W.-Y.; Wang, W.-Y.; Chen, C.-J. Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis. Int. J. Mol. Sci. 2020, 21, 557.

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