Arsenic induces oxidative stress and activates stress gene expressions in cultured lung epithelial cells

✍ Scribed by Muyao Li; Jiu-Feng Cai; Jen-Fu Chiu

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: English
• Weight: 282 KB
• Volume: 87
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.10269

✦ Synopsis

Chronic exposure to low levels of arsenic can cause lung cancer. However, the cellular and molecular mechanisms for lung cell transformation in response to arsenic are not known. These studies investigated the hypothesis that low levels of arsenic increase intracellular oxidant levels, promote production of mitogenic transcription factors and antioxidant enzymes. Initially, arsenic decreased GSH cellular level and rapidly increased to 280% of GSH level in nonexposed lung cells in 24 h. Buthionine sulfoximine (BSO) potentiated the arsenic toxicity of lung epithelial cells (LEC). Exposure of LEC to 5 microM arsenite cause time-dependent increase in gamma-glutamylcysteine synthetase (gamma-GCS) expression. Our data demonstrated that arsenic induced the heavy subunit of gamma-GCS (gamma-GCS-HS) mRNA levels as early as 4 h as compared to the control level. It significantly increased (sixfolds) gamma-GCS-HS mRNA expression after 8 h of treatment. The activation of AP-1 transcription factors may also play a regulatory role in this process. Significant elevations in c-fos and c-jun mRNA levels were observed within 30 min after exposure to arsenic and by enhancement of AP-1 DNA binding activity and transactivation activity. Responsiveness of LEC to oxidative stress caused by arsenic exposure was further evaluated with mobility shift assay involving redox-sensitive transcription factor NF-kappa B. The specificity of binding was verified by an antibody-supershift. The NF-kappa B DNA binding activities increased more than twofold 30 min after exposure to arsenic and returned to control levels after 4 h of treatment. It remains to be determined whether NF-kappa B plays a role in the As-induced apoptosis or alternatively in attempting to protect the cells from As-induced cell death by upregulating the expression of resistance factors.