Zhang Tong-Cun, Schmitt Michael T, Mumford Judy L
National Research Council, 2001 Wisconsin Avenue NW, Washington, DC 20007, USA.
Carcinogenesis. 2003 Nov;24(11):1811-7. doi: 10.1093/carcin/bgg141. Epub 2003 Aug 14.
Telomeres are critical in maintaining chromosome and genomic stability. Arsenic, a human carcinogen as well as an anticancer agent, is known for its clastogenicity. To better understand molecular mechanisms of arsenic actions, we investigated arsenite effects on telomere and telomerase and determined cell growth and apoptosis in HL-60 and HaCaT cells in vitro. Low concentrations (0.1-1 microM in HaCaT and 0.1-0.5 microM in HL-60) of arsenite increased telomerase activity, maintained or elongated telomere length, and promoted cellular proliferation. High concentrations (>1-40 microM) of arsenite decreased telomerase activity, telomere length and induced apoptosis. Results from the studies comparing cell lines with and without telomerase activity suggested that telomerase was involved in arsenic-induced apoptosis. The spin trap agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was effective in protecting the arsenite-induced telomere attrition and apoptosis, suggesting that reactive oxygen species may play an important role in the shortening of telomeres and apoptosis induced by arsenic. These findings suggest the carcinogenic effects of arsenic may be partly attributed to increase in telomerase activity leading to promotion of cell proliferation and its anticancer effects by exerting oxidative stress and leading to telomeric DNA attrition and apoptosis.
端粒对于维持染色体和基因组稳定性至关重要。砷是一种人类致癌物，也是一种抗癌剂，以其致断裂性而闻名。为了更好地理解砷作用的分子机制，我们研究了亚砷酸盐对端粒和端粒酶的影响，并在体外测定了HL-60和HaCaT细胞的细胞生长和凋亡情况。低浓度（HaCaT细胞中为0.1 - 1微摩尔，HL-60细胞中为0.1 - 0.5微摩尔）的亚砷酸盐可增加端粒酶活性，维持或延长端粒长度，并促进细胞增殖。高浓度（>1 - 40微摩尔）的亚砷酸盐可降低端粒酶活性、端粒长度并诱导凋亡。比较有和无端粒酶活性细胞系的研究结果表明，端粒酶参与了砷诱导的凋亡。自旋捕获剂5,5 - 二甲基 - 1 - 吡咯啉 - N - 氧化物（DMPO）可有效保护亚砷酸盐诱导的端粒磨损和凋亡，这表明活性氧可能在砷诱导的端粒缩短和凋亡中起重要作用。这些发现表明，砷致癌作用可能部分归因于端粒酶活性增加导致细胞增殖促进，而其抗癌作用则是通过施加氧化应激导致端粒DNA磨损和凋亡来实现的。
