Vanadate-induced activation of activator protein-1: Role of reactive oxygen species

Min Ding, Jian-Jian Li, Stephen S. Leonard, Jian Ping Ye, Xianglin Shi, Nancy H. Colburn, Vince Castranova, Val Vallyathan

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Abstract

The present study was undertaken to test the hypothesis that the toxicity and carcinogenicity of vanadium might arise from elevation of reactive oxygen species leading to activation of the transcription factor activator protein-1 (AP-1). The AP-1 transactivation response has been implicated as causal in transformation responses to phorbol esters and growth factors. To investigate the possible activity of vanadium in the activation of AP-1, we treated mouse epidermal JB6 P+ cells stably transfected with an AP-1 luciferase reporter plasmid with various concentrations of vanadate. This resulted in concentration-dependent transactivation of AP-1. Superoxide dismutase (SOD) and catalase inhibited AP-1 activation induced by vanadate, indicating the involvement of superoxide anion radical (O2 -.), hydroxyl radical (·OH) and/or H2O2 in the mechanism of vanadate-induced AP-1 activation. However, sodium formate, a specific ·OH scavenger, did not alter vanadate-induced AP-1 activation, suggesting a minimal role for the ·OH radical. NADPH enhanced AP-1 activation by increasing vanadate-mediated generation of O2 -.. N-acetylcysteine, a thiol-containing antioxidant, decreased activation, further showing that vanadate-induced AP-1 activation involved redox reactions. Calphostin C, a specific inhibitor of protein kinase C (PKC), inhibited activation of AP-1, demonstrating that PKC is involved in the cell signal cascades leading to vanadate-induced AP-1 activation. Electron spin resonance (ESR) measurements show that JB6 P+ cells are able to reduce vanadate to generate vanadium(IV) in the presence of NADPH. Molecular oxygen was consumed during the vanadate reduction process to generate O2 -. as measured by ESR spin trapping using 5,5-dimethyl-L-pyrroline N-oxide as the spin trapping agent. SOD inhibited the ESR spin adduct signal, further demonstrating the generation of O2 -. in the cellular reduction of vanadate. These results provide support for a model in which vanadium, like other classes of tumor promoters, transactivates AP-1-dependent gene expression. In the case of vanadium, AP-1 transactivation is dependent on the generation of O2 -. and H2O2, but not ·OH.

Original languageEnglish (US)
Pages (from-to)663-668
Number of pages6
JournalCarcinogenesis
Volume20
Issue number4
StatePublished - 1999
Externally publishedYes

Fingerprint

Vanadates
Transcription Factor AP-1
Reactive Oxygen Species
Vanadium
Hydroxyl Radical
Electron Spin Resonance Spectroscopy
Transcriptional Activation
Spin Trapping
formic acid
NADP
Superoxides
Protein Kinase C
Superoxide Dismutase
Carcinogenicity Tests
Toxicity Tests
Acetylcysteine
Phorbol Esters
Luciferases
Sulfhydryl Compounds
Carcinogens

ASJC Scopus subject areas

  • Cancer Research

Cite this

Ding, M., Li, J-J., Leonard, S. S., Ye, J. P., Shi, X., Colburn, N. H., ... Vallyathan, V. (1999). Vanadate-induced activation of activator protein-1: Role of reactive oxygen species. Carcinogenesis, 20(4), 663-668.

Vanadate-induced activation of activator protein-1 : Role of reactive oxygen species. / Ding, Min; Li, Jian-Jian; Leonard, Stephen S.; Ye, Jian Ping; Shi, Xianglin; Colburn, Nancy H.; Castranova, Vince; Vallyathan, Val.

In: Carcinogenesis, Vol. 20, No. 4, 1999, p. 663-668.

Research output: Contribution to journalArticle

Ding, M, Li, J-J, Leonard, SS, Ye, JP, Shi, X, Colburn, NH, Castranova, V & Vallyathan, V 1999, 'Vanadate-induced activation of activator protein-1: Role of reactive oxygen species', Carcinogenesis, vol. 20, no. 4, pp. 663-668.
Ding M, Li J-J, Leonard SS, Ye JP, Shi X, Colburn NH et al. Vanadate-induced activation of activator protein-1: Role of reactive oxygen species. Carcinogenesis. 1999;20(4):663-668.
Ding, Min ; Li, Jian-Jian ; Leonard, Stephen S. ; Ye, Jian Ping ; Shi, Xianglin ; Colburn, Nancy H. ; Castranova, Vince ; Vallyathan, Val. / Vanadate-induced activation of activator protein-1 : Role of reactive oxygen species. In: Carcinogenesis. 1999 ; Vol. 20, No. 4. pp. 663-668.
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