Down Regulation of hTERT Is an Important Mechanism in Apoptosis of MUTZ-l Cells Induced by As2O3.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenia and by increased progression to acute myeloid leukemia (AML). In this study, MDS cell line MUTZ-1 cells were treated with As2O3 to demonstrate the effects of As2O3 on MDS. We found As2O3 inhibited the proliferation of MUTZ-1 cells in a dose- and time-dependent manner. As2O3 induced apoptosis in MUTZ-1 cells via activation of caspase8, 3 and subsequent cleavage of the DNA repair enzyme pol(ADP-ribose) polymerase(PARP). Subsequently, reduction of NF-kB activity was another important mechanism of As2O3 induced apoptosis in MUTZ-1 cells. Our results also showed that the expression of hTERT mRNA of MUTZ-1 cells was down-regulated by As2O3. Except NF-κB, activity of other nuclear transcription regulator of hTERT, SP-1 and AP-1 were inhibited meanwhile using gel shift assay. Moreover, we further found that NF-κB inhibitor, PDTC, couldn’t activate capase8 but inhibited growth of MUTZ-1 cells and down-regulated hTERT mRNA expression. In addition, caspase8 inhibitor can’t block the reduction of NF-κB activity by As2O3. We concluded that As2O3 could induce apoptosis in MUTZ-1 cells by two independent ways, one is caspase8,3 and PARP activation, the other is inhibition of NF-κB activity subsequent down-regulation of hTERT. hTERT and NF-κB were two important molecular targets in apoptosis induced by As2O3. As2O3 down-regulated hTERT expression via inhibition of NFκB, SP-1 and AP-1.