Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis.

Cheng-Yi Chang,Chih-Cheng Wu,Chun-Jung Chen,Wen-Yi Wang,Su-Lan Liao,Wen-Ying Chen,Jiaan-Der Wang,Jian-Ri Li

doi:10.3390/ijms21020557

Abstract

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.

Highlights

Glioma, glioblastoma multiforme, is the worst and most aggressive central nervous system malignancy [1]
The findings suggest that p38 represents an alternative machinery in mediating indomethacin-induced glioma apoptosis lying upstream of the phosphatase 2A (PP2A)/Akt/Mcl-1 and FLICE-inhibiting protein (FLIP) axis
The current findings indicate that the oxidative stress/endoplasmic reticulum (ER) stress/apoptosis signal-regulating kinase-1 (Ask1)/p38 cascade contributes to indomethacin-induced glioma apoptosis, at least in part, by exerting an effect on the axis of PP2A/Akt/Mcl-1 and FLIP

Summary

Introduction

Glioblastoma multiforme, is the worst and most aggressive central nervous system malignancy [1]. Clinical examination has revealed an elevated expression of Bcl-2 anti-apoptosis family proteins in malignant glioma [3,4,5], implying a crucial role of apoptosis inactivation in glioma drug resistance, poor prognosis, and recurrence. Malignant glioma maintains ER homeostasis with an aim to suppress ER stress-induced apoptotic cell death [8]. ER stress induces glioma cell apoptosis and sensitizes glioma cells to apoptotic treatment [9,10,11,12]. These phenomena indicate that ER stress may be a valuable target for intervention in glioma apoptosis activation

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Discussion

Conclusion