Arsenic inhibition of telomerase transcription leads to genetic instability
Wen-Chien Chou, Anita L. Hawkins, John F. Barrett, Constance A. Griffin, Chi V. Dang
Wen-Chien Chou, Anita L. Hawkins, John F. Barrett, Constance A. Griffin, Chi V. Dang
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Arsenic inhibition of telomerase transcription leads to genetic instability

Abstract

Arsenic is effective in the treatment of acute promyelocytic leukemia. Paradoxically, it is also carcinogenic. In the process of elucidating a mechanism of arsenic resistance in a leukemia cell line, NB4, we discovered that arsenic exposure causes chromosomal abnormalities, with a preponderance of end-to-end fusions. These chromosomal end fusions suggested that telomerase activity may be inhibited by arsenic. We found that arsenic inhibits transcription of the hTERT gene, which encodes the reverse transcriptase subunit of human telomerase. This effect may in part be explained by decreased c-Myc and Sp1 transcription factor activities. Decreased telomerase activity leads to chromosomal end lesions, which promote either genomic instability and carcinogenesis or cancer cell death. These phenomena may explain the seemingly paradoxical carcinogenic and antitumor effects of arsenic.

Authors

Wen-Chien Chou, Anita L. Hawkins, John F. Barrett, Constance A. Griffin, Chi V. Dang

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Arsenic specifically suppresses hTERT mRNA levels independent of cell ty...
Arsenic specifically suppresses hTERT mRNA levels independent of cell type. The expression of hTERT and c-myc was measured by real-time PCR and normalized to actin in b and human phosphoprotein in a, c, and d. hTERT mRNA levels are expressed as percent of untreated control. (a) Arsenic diminished hTERT mRNA expression in a dose-dependent fashion. Experiments were performed after 12 days of arsenic exposure. (b) Two days of arsenic (0.75 μM) but not vincristine (Vin; 0.075 nM) or doxorubicin (Dox; 50 nM) diminishes hTERT mRNA levels. (c) Cell lines other than NB4 also had decreased hTERT mRNA levels after arsenic treatment. NB4 cells were especially sensitive as 0.75 μM for 8 days had resulted in more than 98% inhibition of hTERT expression. The other cell lines were treated with 2 μM arsenic for 14 days. (d) c-myc expression was also decreased in all four cell lines with arsenic exposure.