Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

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.

α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors

“…The amplification of apoptosis and the overall antitumor effect of both COX-1 and COX-2 inhibitors have been repeatedly described for a variety of transformed cells. For example, a non-selective COX inhibitor used in this study, indomethacin, suppressed the growth of human colon adenocarcinoma cells [15], MNNG/HOS osteosarcoma cells [16], human H4 and U87 glioma cells [17], and many other cell lines. The proapoptotic effect of COX inhibitors is associated with both reduced COX catalytic activity and inhibition of PGE2 synthesis, even with COX-independent mechanisms [18,19].…”

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

“…The levels of Mcl-1 and Noxa are regulated at several steps, particularly the transcriptional level [ 27 , 45 , 46 ]. ER stress represents a crucial upstream regulator of the transcription of the Bcl-2 family proteins, either promoting or inhibiting transcription [ 41 , 47 ]. Under stressed situations, the physiological role of ER stress is to restore the organelle’s homeostasis; however, sustained or chronic ER stress can trigger the cell death program via a complex series of biochemical events involving protein phosphorylation and transcription factors.…”

“…Instead of cell death, reduction of cell proliferation and motility is found in aspirin-treated glioblastoma cancer stem cells [ 53 ]. Previously, we reported the role of an apoptotic axis triggered by ER stress, which led to p38 activation and Akt inactivation, resulting in Mcl-1 and FLIP downregulation in indomethacin-treated glioma cells [ 47 ]. The maintenance of ER homeostasis helps to suppress ER stress-induced apoptotic cell death in malignant glioma [ 54 ].…”

Modulation of non-steroidal anti-inflammatory drug-induced, ER stress-mediated apoptosis in Caco-2 cells by different polyphenolic antioxidants: a mechanistic study

“…[ 1,24,25 ] Activation of ER stress signalling PERK/eIF‐2α/ATF‐4/CHOP and/or IRE‐1α/JNK1/2 pathways by indomethacin and diclofenac results in apoptosis in several culture models including primary pig gastric epithelial cells, Huh‐7, H‐4 and U‐87 cells. [ 4,5 ] In this study, we demonstrated that indomethacin and diclofenac caused ER stress‐mediated apoptosis in Caco‐2 cells by activating different arms of ER sensors. These two NSAIDs and the other two known ER stressors tunicamycin and thapsigargin shared a similar apoptosis‐inducing mechanism by activation of PERK/eIF‐2α/ATF‐4/CHOP pathway.…”

“…[ 3 ] Indomethacin and diclofenac have been linked to increased phosphorylation of ER sensors, particularly pancreatic‐like ER kinase (PERK) and inositol‐requiring enzymes‐1α (IRE‐1α), in various cell models such as human glioma cells. [ 4,5 ] Activation of PERK upregulates the C/EBP homologous transcription factor expression (CHOP), resulting in alteration of apoptotic proteins, mitochondrial dysfunction and apoptosis. [ 6,7 ]…”