Arsenic enhances the activation of Stat1 by interferon gamma 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 microM, whereas at a lower concentration of 0.1 microM, a partial differentiation of APL is observed. In non-APL cells, interferon (IFN) alpha and 1 microM 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, IFNalpha or IFNgamma combined with 0.1 microM As2O3 lead to an increased maturation effect. Moreover, IFNgamma 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. IFNgamma 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/RARalpha and PML, did not alter PKR and Stat1, and upregulated interferon regulatory family (IRF)-1. Synergism by IFNgamma and arsenic on IRF-1 expression is mediated by a composite element in the IRF-1 promoter that includes an IFNgamma-activation site (GAS) overlapped by a nonconsensus site for nuclear factor kappa B (NFkappaB). Arsenic has no effect on NFkappaB, whereas it enhances the activation of Stat1 by IFNgamma in NB4 cells leading to an increase in IRF-1 expression.
Chelbi-alix
Mounira K
MK
UPR9045, Institut Lwoff, 7 rue Guy Moquet, 94801 Villejuif, France.
Bobé
Pierre
P
Benoit
Gerard
G
Canova
Antony
A
Pine
Richard
R
D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000633:toxicity*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute; D010087:Oxides / Q000633:toxicity*; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014212:Tretinoin / Q000633:toxicity; D014407:Tumor Cells, Cultured
D001152:Arsenicals; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010087:Oxides; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D013481:Superoxides; D014212:Tretinoin; D007371:Interferon-gamma; D001151:Arsenic; D000077237:Arsenic Trioxide