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ARSENIC EFFECTS ON TELOMERE AND TELOMERASE ACTIVITY
Citation:
Zhang, T., J. Mo, J. S. Mumford, AND M Schmitt. ARSENIC EFFECTS ON TELOMERE AND TELOMERASE ACTIVITY. Presented at American Assoc. for Cancer Research (AACR) Meeting, Orlando, FL, March 21-27, 2004.
Description:
Arsenic effects on telomere and telomerase activity. T-C. Zhang, M. T. Schmitt, J. Mo, J. L. Mumford, National Research Council and U.S Environmental Protection Agency, NHEERL, Research Triangle Park, NC 27711
Arsenic is a known carcinogen and also an anticancer agent for acute promyelocytic leukemia in humans. The mechanisms of these effects by arsenic are largely unknown. Since arsenic has been shown to be a clastogen, one possible mechanism of arsenic effects is associated with induction of chromosomal abnormalities by arsenic. Telomeres play a critical role in maintaining chromosome stability. In this study, we examined the effects of arsenite on telomere length and telomerase (hTERT) activity, cell proliferation and apoptosis in HaCaT (human epidermal keratinocytes) and HL-60 cells (human acute promyelocytic leukemia) in vitro. Cell viability and total cell number were determined by MTT assays and trypan blue, following treatment of sodium arsenite at 0.1-40 ?M for 1-5 days. Apoptosis was determined by Hoechst/PI nuclei staining and DNA ladder assay. Telomere length was determined by telomere restriction fragment (TRF) analysis. Telomerase activity and hTERT protein expression was detected by TRAP and immunohistochemistry staining, respectively. A scavenger of reactive oxygen species (ROS), 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was added to the arsenic treated cells to investigate the role of ROS in arsenic effects. Results showed that arsenite induced cell proliferation at low doses, while inhibited cell growth and induced apoptosis at high doses. Low concentrations (0.1-1?M in HaCaT and 0.1-0.5?M in HL-60) of arsenite increased telomerase activity, maintained or elongated telomere length, and correspondingly promoted cellular proliferation. High concentrations (>1-40?M) of arsenite decreased telomerase activity and telomere length and, correspondingly, induced apoptosis. DMPO studies suggested that ROS may play an important role in shortening of telomeres and apoptosis induced by arsenic. Other possible modes of action are under investigation and will be reported. The study results demonstrated that arsenite altered telomerase activity and telomere length, that were associated with cell proliferation and apoptosis in human cells. These findings suggest the carcinogenic effects of arsenic may be partly attributed to an increase in telomerase activity leading to promotion of cell proliferation while its anticancer effects may be attributed to exerting oxidative stress and leading to telomeric DNA attrition and apoptosis. (This abstract does not reflect EPA policy.)