Downregulation of hTERT: An Important As(2)O(3) Induced Mechanism of Apoptosis in Myelodysplastic Syndrome

Two myelodysplastic syndrome (MDS) celllines, MUTZ-1 and SKM-1 cells, were used to study the effect of arsenic trioxide (As(2)O(3)) on hematological malignant cells. As(2)O(3) induced this two cell lines apoptosis via activation of caspase-3/8 and cleavage of poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme. As(2)O(3) reduced NF-κB activity, which was important for inducing MUTZ-1 and SKM-1 cells apoptosis. As(2)O(3) also inhibited the activities of hTERT in MUTZ-1 and SKM-1 cells. Moreover, the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), had no effect on caspase-8 activation, although PDTC did inhibit MUTZ-1 and SKM-1 cells proliferation. Incubation of MUTZ-1 cells with a caspase-8 inhibitor failed to block As(2)O(3)-induced inhibition of NF-κB activity. Our findings suggest that As(2)O(3) may induce apoptosis in MUTZ-1 and SKM-1 cells by two independent pathways: first, by activation of caspase-3/8 and PARP; and second, by inhibition of NF-κB activity, which results in downregulation of hTERT expression. We conclude that hTERT and NF-κB are important molecular targets in As(2)O(3)-induced apoptosis.