Overexpression of human
telomere repeat binding factor 2 (TRF2), which may play an important role in the fate of
cancer cells, has been observed in
adult T-cell leukemia. Previous reports have shown that the inhibition of TRF2 results in the apoptosis of
cancer cells. In this study, we demonstrated that
arsenic trioxide (
As2O3) induced in vitro growth inhibition and/or apoptosis of human
T-cell leukemia cell line Molt-4 in a
caspase-independent manner.
Telomerase activity was not inhibited, although the level of the
reverse transcriptase subunit of the human
telomerase gene (hTERT)
mRNA expression was down regulated during the early times and then recovered to the level found in untreated controls about 48 hours
after treatment with
As2O3. Furthermore, a remarkable telomere shortening related to exposure of
As2O3 was observed in 50 population doubling. Inc ontrast, the alteration of telomere length did not occur after exposure to higher concentration of
As2O3 (10 microM) for 24 hours and 48 hours, respectively, suggesting that the shortening of telomeres induced by
As2O3 is dependent of a series of cell division cycles. Chromosomal analysis showed that
As2O3 exposure caused chromosomal end-to-end fusion in human
T-cell leukemia cells while downregulation of TRF2 was observed. Finally, the inhibition of
TRF2 protein expression and the sensitivity to
As2O3 in a panel of
leukemia cell lines were checked. The data revealed that inhibition of TRF2 rendered
leukemia cells more susceptible to
As2O3. In conclusion, the downregulation of TRF2 by
As2O3 contribute to chromosomal end-to-end fusion, and apoptosis in
leukemia cells, suggesting that TRF2 could be an attractive target for new
therapies of
leukemia.