Arsenic enhances the activation of Stat1 by interferon ? leading to synergistic expression of IRF-1.

Arsenic trioxide (As₂O₃) can induce clinical remission in patients with acute promyelocytic leukemia (APL), including those who have relapsed after treatment with all-trans-retinoic acid (RA). In vitro studies with the APL-derived NB4 cell line showed that As₂O₃ exerts a dose-dependent dual effect, which induces apoptosis at 1?µM, whereas at a lower concentration of 0.1?µM, a partial differentiation of APL is observed. In non-APL cells, interferon (IFN) a and 1?µM As₂O₃ act synergistically to induce apoptosis. In this report, we show that in NB4 cells and in two RA-resistant NB4-derived cell lines, NB4-R1 and NB4-R2, IFNa or IFN? combined with 0.1?µM As₂O₃ lead to an increased maturation effect. Moreover, IFN? alone is able to differentiate RA-sensitive and -resistant cells with a higher maturation effect on NB4-R2 cells. In contrast, all these cells underwent apoptosis in the presence of the cytokine and a higher concentration of As₂O₃. IFN? boosted As₂O₃-induced apoptosis in APL cells as tested by TUNEL, Annexin V staining and activation of caspase 3. As₂O₃ differently altered IFN-induced gene products; it downregulated PML/RARa and PML, did not alter PKR and Stat1, and upregulated interferon regulatory family (IRF)-1. Synergism by IFN? and arsenic on IRF-1 expression is mediated by a composite element in the IRF-1 promoter that includes an IFN?-activation site (GAS) overlapped by a nonconsensus site for nuclear factor kappa B (NF?B). Arsenic has no effect on NF?B, whereas it enhances the activation of Stat1 by IFN? in NB4 cells leading to an increase in IRF-1 expression.Oncogene (2003) 22, 9121-9130. doi:10.1038/sj.onc.1207090 [ABSTRACT FROM AUTHOR]