Indomethacin Sensitizes TRAIL-Resistant Melanoma Cells to TRAIL-Induced Apoptosis through ROS-Mediated Upregulation of Death Receptor 5 and Downregulation of Survivin

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted considerable attention owing to its selective killing of tumor cells but not normal cells. Melanoma shows weak response to TRAIL because of its low level of TRAIL death receptors. Here, we investigated whether indomethacin, a nonsteroidal anti-inflammatory drug, can potentiate TRAIL-induced apoptosis in melanoma cells. We showed that indomethacin was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. Mechanistically, indomethacin induced cell surface expression of death receptor 5 (DR5) in melanoma cells and also in various types of cancer cells. DR5 knockdown abolished the enhancing effect of indomethacin on TRAIL responses. Induction of the DR5 by indomethacin was found to be p53 independent but dependent on the induction of CCAAT/enhancer-binding protein homologous protein (CHOP). Knockdown of CHOP abolished indomethacin-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, indomethacin-induced reactive oxygen species (ROS) production preceded upregulation of CHOP and DR5, and consequent sensitization of cells to TRAIL. We also found that indomethacin treatment downregulated survivin via ROS and the NF-κB-mediated signaling pathways. Interestingly, indomethacin also converted TRAIL-resistant melanoma MeWo and SK-MEL-5 cells into TRAIL-sensitive cells. Taken together, our results indicate that indomethacin can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of survivin.

TRAIL Enhances Shikonin Induced Apoptosis through ROS/JNK Signaling in Cholangiocarcinoma Cells

“…Finally, caspase-3 protein expression and apoptosis induced by shikonin plus TRAIL were significantly attenuated after cells transfected with Si-DR5, and cell viability in same treatment could significantly promote compared with control. Previous study demonstrated that DR5 could induce JNK activation in colon cells [45], whereas most of other studies showed that ROS/JNK signalling mediated DR5 in various cell lines [46, 47], which were consistent with our results. In addition, we also found that Si-DR5 transfection has no effect on shikonin induced cell death.…”

“…In addition, we also found that Si-DR5 transfection has no effect on shikonin induced cell death. This findings were similar to previous study [47]. These results suggested that shikonin-induced DR5 up-regulation was essential for TRAIL-enhanced effects of shikonin in RBE cells.…”

Matrine‐Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species‐Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling

“…ROS participates in many intracellular pathological changes 6, 7. In accord with our and other previous studies, ROS triggers programmed cell death through the mitochondrial pathway, death receptor pathway, and endoplasmic reticulum stress‐mediated pathway 8, 9, 10. Previous studies indicated that AGEs induced endothelial cell apoptosis by exacerbating ROS‐mediated apoptosis 11…”

Goniothalamin enhances TRAIL-induced apoptosis in colorectal cancer cells through DR5 upregulation and cFLIP downregulation

“…Natural compounds such as kurarinone (20), icaritin (21), withanolide E (22) were reported to downregulate cFLIP expression and subsequent sensitization of TRAIL-resistant cancer cells to TRAIL-induced apoptosis. Natural compounds, such as silibinin (23), gingerol (24) and indomethacin (25) were reported to possess both mechanisms of sensitizing TRAIL-resistant cancer cells.…”