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.
AffiliationDepartment of Pharmacology and Therapeutics, Clinical Science Building, Cork, University Hospital, Cork, Ireland.
Antineoplastic Agents/pharmacology/*therapeutic use
Apoptosis Inducing Factor/metabolism
Apoptosis Regulatory Proteins/genetics
Carcinoma, Renal Cell/*drug therapy/enzymology
Cell Line, Tumor
Gene Expression/drug effects
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
MetadataShow full item record
CitationMol Pharmacol. 2006 Jun;69(6):1879-90. Epub 2006 Mar 16.
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.
- Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT.
- Authors: Ou YC, Yang CR, Cheng CL, Raung SL, Hung YY, Chen CJ
- Issue date: 2007 Jun 1
- MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway.
- Authors: Ying M, Tu C, Ying H, Hu Y, He Q, Yang B
- Issue date: 2008 Jun
- Protein kinase C-ERK1/2 signal pathway switches glucose depletion-induced necrosis to apoptosis by regulating superoxide dismutases and suppressing reactive oxygen species production in A549 lung cancer cells.
- Authors: Kim CH, Han SI, Lee SY, Youk HS, Moon JY, Duong HQ, Park MJ, Joo YM, Park HG, Kim YJ, Yoo MA, Lim SC, Kang HS
- Issue date: 2007 May
- Targeting beta2-microglobulin mediated signaling as a novel therapeutic approach for human renal cell carcinoma.
- Authors: Nomura T, Huang WC, Seo S, Zhau HE, Mimata H, Chung LW
- Issue date: 2007 Jul
- Sulindac-derived reactive oxygen species induce apoptosis of human multiple myeloma cells via p38 mitogen activated protein kinase-induced mitochondrial dysfunction.
- Authors: Seo SK, Lee HC, Woo SH, Jin HO, Yoo DH, Lee SJ, An S, Choe TB, Park MJ, Hong SI, Park IC, Rhee CH
- Issue date: 2007 Jan