Effects and Interactions of Low Doses of Arsenic and Uvb on Keratinocyte Apoptosis
Resource
CHEMICAL RESEARCH IN TOXICOLOGY v.17 n.9 pp.1199~1205
Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Journal Volume
v.17
Journal Issue
n.9
Pages
1199-1205
Date Issued
2004
Date
2004
Author(s)
LEE, CHIH-HUNG
YU, CHIA-LI
Abstract
Although arsenic and ultraviolet light B (UVB) are both causes for skin cancers, lesions of arsenic-induced Bowen's disease are often confined to sun-protected skin. UVB may play a modulatory role in skin carcinogenesis by arsenic. The purpose of this study was to evaluate the effects and interactions of arsenic and UVB on cell cycle progression and apoptosis. Cultured human keratinocytes were treated with sodium arsenite (1 muM) and /or UVB (50 mJ/cm(2)) irradiation in different combinations: (i) arsenic alone, ( ii) UVB alone, (iii) arsenic followed by UVB (As-UVB), and ( iv) UVB followed by arsenic (UVB-As) treatments. Cell cycle analysis and BrdU pulsing revealed S phase arrest in all treatment groups and growth arrest in As-UVB and UVB-As groups. The terminal deoxynucleotidyl transferase- mediated deoxyuridine nick-end labeling assay showed a higher apoptosis rate in the UVB-As group as compared to that of the As-UVB and UVB groups. UVB irradiation significantly decreased Bcl-2 expression. In either the As-UVB or the UVB- As group, the expression of Bcl-2 was further suppressed as compared to the UVB group. The caspase-3, -8, and -9 relative activities were all increased in the UVB group; however, arsenic significantly enhanced caspase-8 and -3 relative activities in UVB- irradiated keratinocytes (the UVB -As group). Pretreatment with the caspase inhibitor(s) rescued the keratinocytes viability to different degrees with the least in the UVB-As group. Our findings revealed that arsenic enhances UVB-induced keratinocyte apoptosis via suppression of Bcl -2 expression and stimulation of caspase- 8 activity. Combined UVB and arsenic treatment resulted in the antiproliferative and proapoptotic effects in keratinocytes. Our results provide the explanation for the rare occurrences of arsenical cancers in the sun-exposed skin and the potential therapeutic role of UVB in arsenic- induced Bowen's disease.
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