Human malignant mesothelioma cell growth: activation of janus kinase 2 and signal transducer and activator of transcription 1alpha for inhibition by interferon-gamma.
Intrapleural injections of recombinant human IFN-gamma have shown some efficacy in reducing tumor growth in early stages of diffuse malignant mesothelioma (DMM). Here, we have addressed the potential therapeutic effect of IFN-gamma in DMM by investigating the activation of the JAK/STAT signaling pathway in seven human mesothelioma cell lines (HMCLs) that were differentially responsive to the antiproliferative activity of IFN-gamma. We showed that janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) were phosphorylated on tyrosine residues within 15 min in all the HMCLs in which IFN-gamma (500 units/ml) inhibited proliferation. In addition, STAT1 binding activity to the gamma-activated sites DNA sequence was detected within 15 min in electrophoretic mobility-shift assay analysis, and IFN regulatory factor-1 RNA expression was observed within 6 h in the more responsive cells (72.7-95.2% inhibition of DNA synthesis after 72 h of treatment). Conversely, in several HMCLs, absent or limited growth suppressive effect (less than 22% inhibition of DNA synthesis) was associated with alterations in expression or activation of JAK2 or STAT1 or, downstream, with low induction of IFN regulatory factor-1 RNA expression and/or STAT1 protein expression following IFN-gamma treatment. These data suggest that at least part of the IFN-gamma effect on proliferation of HMCLs is mediated directly through activation of the JAK/STAT1 signaling pathway, and it could account for the antitumoral activity reported in DMM patients treated with IFN-gamma.
Buard
A
A
Institut National de la Santé et de la Recherche Médicale U139, Faculté de Médecine, Créteil, France.
Vivo
C
C
Monnet
I
I
Boutin
C
C
Pilatte
Y
Y
Jaurand
M C
MC
D002455:Cell Division; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004789:Enzyme Activation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2; D008654:Mesothelioma / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2