Interaction of cigarette smoke component NNK and arsenic in enhancement of lung carcinogenic risk

[[abstract]]Interaction of cigarette smoke component NNK and arsenic in enhancement of lung cancer risk. Louis W. Chang, W.T. Liao, H.S. Yu, and Pinpin Lin. National Health Research Institutes and Kaohsiung Medical University, Taiwan, ROC. Epidemiological evidence indicates that there is a significant enhancement in lung cancer incidence among cigarette smokers in arseniasis areas as compared to that in the general population, suggesting a synergism for lung carcinogenesis between cigarette smoke and arsenic. Reduced p53 status in bronchiolar epithelial cells is found in cigarette smokers. We hypothesize that reduced p53 status (reduced p53 expression, activity, or function) provides the stage for arsenic to promote genomic and chromosomal instability (such as centrosome abnormality) leading to an increase in carcinogenic risk. We treated immortalized human bronchiolar epithelial cells (BEAS-2B) with or without p53 inhibitor (pifithrin) as well as a human lung cancer cell line (H1355), which is known to have p53 mutation, with 1-10 uM of arsenite. We found that arsenic treated cells were more resistant to apoptosis. Furthermore, cells with suppressed p53 status (e.g., pif.-treated BEAS-2B cells) showed a reduced Gadd45a expression and an increased centrosome abnormality (centrosome amplification). An increase in cell colony formation by these cells was also observed. These observations clearly indicate that lowered p53 status provides a stage for arsenic to suppress Gadd45a, which is important for the maintenance of centrosome stability and integrity. With suppression of Gadd45a, arsenic would then promote centrosome abnormality with enhanced cell transformation. We further demonstrated that NNK, a specific component in cigarette smoke, suppressed p53 activity in BEAS-2B cells in a dose depending manner. Co-treatment of NNK (1-5 uM) and arsenite (1-5 uM) also showed dose-corresponded increases in chromosome abnormality (amplification) and cellular anueploidy in BEAS-2B cells. These findings further provide the needed scientific validation, as suggested by epidemiological studies, that there is a synergistic interaction between cigarette smoke (NNK) and arsenic in the enhancement of lung carcinogenic risk