Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor.

Hdl Handle:
http://hdl.handle.net/10147/208858
Title:
Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor.
Authors:
Ambrose, Monica; Ryan, Aideen; O'Sullivan, Gerald C; Dunne, Colum; Barry, Orla P
Affiliation:
Department of Pharmacology and Therapeutics, Clinical Science Building, Cork, University Hospital, Cork, Ireland.
Citation:
Mol Pharmacol. 2006 Jun;69(6):1879-90. Epub 2006 Mar 16.
Journal:
Molecular pharmacology
Issue Date:
3-Feb-2012
URI:
http://hdl.handle.net/10147/208858
DOI:
10.1124/mol.105.020875
PubMed ID:
16543392
Abstract:
Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH(2)-terminal kinase or p38alpha and -beta mitogen-activated protein kinase activation. In contradiction, reintroduction of p38delta by stable transfection or overexpression of p38gamma dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x(L) and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl l-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.
Language:
eng
MeSH:
Aminoquinolines/pharmacology/*therapeutic use; Antineoplastic Agents/pharmacology/*therapeutic use; *Apoptosis; Apoptosis Inducing Factor/metabolism; Apoptosis Regulatory Proteins/genetics; Carcinoma, Renal Cell/*drug therapy/enzymology; Cell Line, Tumor; Cyclooxygenase 2/metabolism; Down-Regulation; Gene Expression/drug effects; Humans; Kidney Neoplasms/*drug therapy/enzymology; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 12/metabolism; Mitogen-Activated Protein Kinase 13/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Protein Transport/drug effects; Reactive Oxygen Species/analysis/*metabolism
ISSN:
0026-895X (Print); 0026-895X (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorAmbrose, Monicaen_GB
dc.contributor.authorRyan, Aideenen_GB
dc.contributor.authorO'Sullivan, Gerald Cen_GB
dc.contributor.authorDunne, Columen_GB
dc.contributor.authorBarry, Orla Pen_GB
dc.date.accessioned2012-02-03T15:05:39Z-
dc.date.available2012-02-03T15:05:39Z-
dc.date.issued2012-02-03T15:05:39Z-
dc.identifier.citationMol Pharmacol. 2006 Jun;69(6):1879-90. Epub 2006 Mar 16.en_GB
dc.identifier.issn0026-895X (Print)en_GB
dc.identifier.issn0026-895X (Linking)en_GB
dc.identifier.pmid16543392en_GB
dc.identifier.doi10.1124/mol.105.020875en_GB
dc.identifier.urihttp://hdl.handle.net/10147/208858-
dc.description.abstractRenal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH(2)-terminal kinase or p38alpha and -beta mitogen-activated protein kinase activation. In contradiction, reintroduction of p38delta by stable transfection or overexpression of p38gamma dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x(L) and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl l-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.en_GB
dc.language.isoengen_GB
dc.subject.meshAminoquinolines/pharmacology/*therapeutic useen_GB
dc.subject.meshAntineoplastic Agents/pharmacology/*therapeutic useen_GB
dc.subject.mesh*Apoptosisen_GB
dc.subject.meshApoptosis Inducing Factor/metabolismen_GB
dc.subject.meshApoptosis Regulatory Proteins/geneticsen_GB
dc.subject.meshCarcinoma, Renal Cell/*drug therapy/enzymologyen_GB
dc.subject.meshCell Line, Tumoren_GB
dc.subject.meshCyclooxygenase 2/metabolismen_GB
dc.subject.meshDown-Regulationen_GB
dc.subject.meshGene Expression/drug effectsen_GB
dc.subject.meshHumansen_GB
dc.subject.meshKidney Neoplasms/*drug therapy/enzymologyen_GB
dc.subject.meshMitogen-Activated Protein Kinase 1/metabolismen_GB
dc.subject.meshMitogen-Activated Protein Kinase 12/metabolismen_GB
dc.subject.meshMitogen-Activated Protein Kinase 13/metabolismen_GB
dc.subject.meshMitogen-Activated Protein Kinase 3/metabolismen_GB
dc.subject.meshProtein Transport/drug effectsen_GB
dc.subject.meshReactive Oxygen Species/analysis/*metabolismen_GB
dc.titleInduction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor.en_GB
dc.contributor.departmentDepartment of Pharmacology and Therapeutics, Clinical Science Building, Cork, University Hospital, Cork, Ireland.en_GB
dc.identifier.journalMolecular pharmacologyen_GB
dc.description.provinceMunster-
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