Effects of arsenic on telomerase and telomeres in relation to cell proliferation and apoptosis in human keratinocytes and leukemia cells in vitro.
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.
Zhang
Tong-Cun
TC
National Research Council, 2001 Wisconsin Avenue NW, Washington, DC 20007, USA.
Schmitt
Michael T
MT
Mumford
Judy L
JL
D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000473:pathology*; D013113:Spin Labels; D019098:Telomerase / Q000187:drug effects*; D016615:Telomere / Q000187:drug effects*
D003497:Cyclic N-Oxides; D013113:Spin Labels; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D019098:Telomerase; D001151:Arsenic