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Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT.
Eur J Pharmacol. 2007 Jun 01; 563(1-3):49-60.EJ

Abstract

Studies on chemoprevention of cancer are generating increasing interest. The anti-neoplastic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) involves cyclooxygenase (COX)-dependent and COX-independent mechanisms. Evidence suggests that mitogen-activated protein kinases (MAPKs) may mediate apoptotic signaling induced by anti-neoplastic agents. While many reports have revealed the existence of MAPK activation in apoptosis induced by various stimuli, the signaling transduction pathways used by NSAIDs to trigger apoptosis in human renal cell carcinoma (RCC) remain largely unknown. Treatment of RCC 786-O cells with indomethacin resulted in growth regression and apoptosis. Caspase-dependent apoptosis was evidenced by the detection of enzymatic activities of caspase-3, caspase-6, and caspase-9 and suppression of toxicity using a caspase inhibitor. Indomethacin treatment was associated with increased expression of glucose-regulated protein 78 (GRP78) and C/EBP homologus protein (CHOP) and activation of ATF-6, characteristics of endoplasmic reticulum stress. In addition, the concomitant induction of peroxisome proliferator-activated receptor (PPAR), especially PPAR-beta, was apparent in treated cells. Western blotting revealed the activation of extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) with indomethacin treatment. Selective inhibitors of ERK, p38 MAPK, and JNK suppressed the induction of GRP78, CHOP, and PPAR-beta, attenuated indomethacin-induced cytotoxicity and reduced increased caspase activity. LY294002, a phosphoinositide-3 kinase (PI3K)/AKT inhibitor, and Trolox, an antioxidant, suppressed indomethacin-induced cytotoxicity and caspase activation. Furthermore, Trolox attenuated indomethacin-induced increased phosphorylation in ERK, p38 MAPK, JNK, and AKT. In conclusion, our findings establish a mechanistic link between the oxidative stress, PI3K/AKT pathway, MAPK pathway and indomethacin-induced cellular alterations and apoptosis in 786-O cells.

Authors+Show Affiliations

Ou YC
Division of Urology, Department of Education and Research, Taichung Veterans General Hospital, and Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan.
Yang CR
No affiliation info available
Cheng CL
No affiliation info available
Raung SL
No affiliation info available
Hung YY
No affiliation info available
Chen CJ
No affiliation info available

MeSH

Activating Transcription Factor 6Anti-Inflammatory Agents, Non-SteroidalAntineoplastic AgentsApoptosisCarcinoma, Renal CellCaspasesCell Line, TumorCell SurvivalDose-Response Relationship, DrugEndoplasmic ReticulumEndoplasmic Reticulum Chaperone BiPEnzyme ActivationExtracellular Signal-Regulated MAP KinasesHeat-Shock ProteinsHumansIndomethacinKidney NeoplasmsMAP Kinase Kinase 4MAP Kinase Signaling SystemMitogen-Activated Protein KinasesMolecular ChaperonesOxidative StressPeroxisome Proliferator-Activated ReceptorsPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktReactive Oxygen SpeciesTime FactorsTranscription Factor CHOPUp-Regulationp38 Mitogen-Activated Protein Kinases

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17341418

Citation

Ou, Yen-Chuan, et al. "Indomethacin Induces Apoptosis in 786-O Renal Cell Carcinoma Cells By Activating Mitogen-activated Protein Kinases and AKT." European Journal of Pharmacology, vol. 563, no. 1-3, 2007, pp. 49-60.
Ou YC, Yang CR, Cheng CL, et al. Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT. Eur J Pharmacol. 2007;563(1-3):49-60.
Ou, Y. C., Yang, C. R., Cheng, C. L., Raung, S. L., Hung, Y. Y., & Chen, C. J. (2007). Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT. European Journal of Pharmacology, 563(1-3), 49-60.
Ou YC, et al. Indomethacin Induces Apoptosis in 786-O Renal Cell Carcinoma Cells By Activating Mitogen-activated Protein Kinases and AKT. Eur J Pharmacol. 2007 Jun 1;563(1-3):49-60. PubMed PMID: 17341418.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT. AU - Ou,Yen-Chuan, AU - Yang,Chi-Rei, AU - Cheng,Chen-Li, AU - Raung,Shue-Ling, AU - Hung,Yu-Yeh, AU - Chen,Chun-Jung, Y1 - 2007/02/08/ PY - 2006/11/17/received PY - 2007/1/24/revised PY - 2007/1/24/accepted PY - 2007/3/8/pubmed PY - 2007/8/4/medline PY - 2007/3/8/entrez SP - 49 EP - 60 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 563 IS - 1-3 N2 - Studies on chemoprevention of cancer are generating increasing interest. The anti-neoplastic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) involves cyclooxygenase (COX)-dependent and COX-independent mechanisms. Evidence suggests that mitogen-activated protein kinases (MAPKs) may mediate apoptotic signaling induced by anti-neoplastic agents. While many reports have revealed the existence of MAPK activation in apoptosis induced by various stimuli, the signaling transduction pathways used by NSAIDs to trigger apoptosis in human renal cell carcinoma (RCC) remain largely unknown. Treatment of RCC 786-O cells with indomethacin resulted in growth regression and apoptosis. Caspase-dependent apoptosis was evidenced by the detection of enzymatic activities of caspase-3, caspase-6, and caspase-9 and suppression of toxicity using a caspase inhibitor. Indomethacin treatment was associated with increased expression of glucose-regulated protein 78 (GRP78) and C/EBP homologus protein (CHOP) and activation of ATF-6, characteristics of endoplasmic reticulum stress. In addition, the concomitant induction of peroxisome proliferator-activated receptor (PPAR), especially PPAR-beta, was apparent in treated cells. Western blotting revealed the activation of extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) with indomethacin treatment. Selective inhibitors of ERK, p38 MAPK, and JNK suppressed the induction of GRP78, CHOP, and PPAR-beta, attenuated indomethacin-induced cytotoxicity and reduced increased caspase activity. LY294002, a phosphoinositide-3 kinase (PI3K)/AKT inhibitor, and Trolox, an antioxidant, suppressed indomethacin-induced cytotoxicity and caspase activation. Furthermore, Trolox attenuated indomethacin-induced increased phosphorylation in ERK, p38 MAPK, JNK, and AKT. In conclusion, our findings establish a mechanistic link between the oxidative stress, PI3K/AKT pathway, MAPK pathway and indomethacin-induced cellular alterations and apoptosis in 786-O cells. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17341418/Indomethacin_induces_apoptosis_in_786_O_renal_cell_carcinoma_cells_by_activating_mitogen_activated_protein_kinases_and_AKT_ DB - PRIME DP - Unbound Medicine ER -
Grapherence [↓22]

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