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

Authors
Ding-M; Li-JJ; Leonard-SS; Ye-JP; Shi-X; Colbunr-NH; Castranova-V; Vallyathan-V
Source
Carcinogenesis 1999 May; 20(4):663-668
NIOSHTIC No.
20000963
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.
Keywords
Biological-systems; Carcinogenicity; Vanadium-compounds; Cancer; In-vitro-studies;
Contact
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505
CODEN
CRNGDP
Publication Date
19990501
Document Type
Journal Article;
Email Address
vav1@cdc.gov
Fiscal Year
1999
NTIS Accession No.
NTIS Price
Issue of Publication
4
ISSN
0143-3334
NIOSH Division
HELD;
Priority Area
Disease and Injury; Work Environment and Workforce;
Source Name
Carcinogenesis
State
WV; MD;
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