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Arsenic inhibition of telomerase transcription leads to genetic instability

W C Chou1, A L Hawkins, J F Barrett

  • 1Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

The Journal of Clinical Investigation
|November 21, 2001
PubMed

Insights

Arsenic exposure causes chromosomal abnormalities and inhibits human telomerase (hTERT) gene transcription, potentially explaining its dual role as both a cancer treatment and carcinogen.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Arsenic compounds are utilized in treating acute promyelocytic leukemia.
  • Arsenic also exhibits carcinogenic properties, presenting a paradoxical effect.
  • Understanding arsenic resistance mechanisms in leukemia is crucial.

Purpose of the Study:

  • To elucidate the mechanism of arsenic resistance in the NB4 leukemia cell line.
  • To investigate the impact of arsenic exposure on chromosomal stability and telomerase activity.
  • To explain the paradoxical carcinogenic and antitumor effects of arsenic.

Main Methods:

  • Exposure of NB4 leukemia cells to arsenic.
  • Analysis of chromosomal abnormalities, specifically end-to-end fusions.
  • Assessment of human telomerase reverse transcriptase (hTERT) gene transcription.
  • Evaluation of c-Myc and Sp1 transcription factor activities.

Main Results:

  • Arsenic exposure induced chromosomal abnormalities, predominantly end-to-end fusions.
  • Arsenic was found to inhibit hTERT gene transcription.
  • Decreased activity of c-Myc and Sp1 transcription factors was observed.
  • Inhibition of telomerase activity leads to chromosomal end lesions.

Conclusions:

  • Arsenic-induced inhibition of human telomerase (hTERT) transcription, possibly via reduced c-Myc and Sp1 activity, contributes to chromosomal instability.
  • This chromosomal instability may drive either cancer cell death or genomic instability and carcinogenesis.
  • The findings provide a molecular basis for arsenic's dual role in cancer therapy and carcinogenesis.

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