Arsenic enhances the apoptosis induced by interferon gamma: key role of IRF-1.
Interferons (IFNs) and arsenic trioxide (As2O3) are known inhibitors of cell proliferation and have been used in the treatment of certain forms of malignancy. IFNgamma treatment of cells leads to tyrosine phosphorylation of STAT1 followed by dimerization that accumulates in the nucleus. This is followed by DNA binding, activation of target gene transcription, dephosphorylation, and return to the cytoplasm. We have shown earlier that IFNgamma and As2O3 act synergistically in acute promyelocytic leukemia cells to upregulate IRF-1 expression and to induce apoptosis. Here, we show that in the human fibrosarcoma cell line 2fTGH, As2O3 prolongs IFNgamma-induced STAT1 phosphorylation resulting in persistent binding of STAT1 to GAS motif leading to an increase in IRF-1 expression which correlated with both higher anti-proliferative effect and increased apoptosis. These biological responses induced by IFNgamma alone or in combination with As2O3 were abolished when IRF-1 expression was down-regulated by RNA interference, thus demonstrating the key role of IRF-1.
El Bougrini
J
J
UPR CNRS 9045, Institut André Lwoff 7 rue Guy Moquet, 94801 Villejuif, France.
Pampin
M
M
Chelbi-Alix
M K
MK
D020816:Amino Acid Motifs; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D058851:GPI-Linked Proteins; D015870:Gene Expression / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; D006131:Growth Inhibitors; D050856:Interferon Regulatory Factor-1; D008565:Membrane Proteins; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D001151:Arsenic