Human malignant mesothelioma cell growth: activation of janus kinase 2 and signal transducer and activator of transcription 1alpha for inhibition by interferon-gamma

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 4; pp. 840 - 847
• Main Authors: Buard, A, Vivo, C, Monnet, I, Boutin, C, Pilatte, Y, Jaurand, M C
• Format: Journal Article
• Language: English
• Published: United States 15.02.1998
• Subjects: Cell Division; DNA-Binding Proteins - biosynthesis; Enzyme Activation; Humans; Interferon-gamma - pharmacology; Janus Kinase 2; Mesothelioma - metabolism; Protein-Tyrosine Kinases - biosynthesis; Proto-Oncogene Proteins; Recombinant Proteins; Signal Transduction; STAT1 Transcription Factor; Trans-Activators - biosynthesis; Tumor Cells, Cultured
• ISSN: 0008-5472

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.