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

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Abstract
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 M, whereas at a lower concentration of 0.1 M, a partial differentiation of APL is observed. In non-APL cells, interferon (IFN) and 1 M 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, IFN or IFN combined with 0.1 M 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/RAR 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 (NFB). Arsenic has no effect on NFB, whereas it enhances the activation of Stat1 by IFN in NB4 cells leading to an increase in IRF-1 expression.