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926 Transcription factor STAT3 is a potential therapeutic target in bladder cancer
926
Transcription factor STAT3 is a potential therapeutic target in bladder cancer Eur Urol Suppl 2016;15(3);e926
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Schmid S.C., Yousef A., Sathe A., Horn T., Maurer T., Retz M., Gschwend J.E., Holm P.S., Nawroth R. Technische Universität München, Dept. of Urology, Munich, Germany INTRODUCTION & OBJECTIVES: STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor implicated in cell growth, cell cycle and apoptosis. We analysed the potential of STAT3 as therapeutic target in bladder cancer, using the selective STAT3Inhibitor Stattic. MATERIAL & METHODS: We assessed the effect of Stattic on cell viability in vitro in 20 bladder cancer cell lines. The combination index for combination therapy with cisplatin, gemcitabine, paclitaxel or docetaxel was performed. Immunoblotting and immunofluorescence was used to determine protein expression, phosphorylation and subcellular localization of selected proteins (STAT3, Cyclin D1). Expression of downstream targets was analysed using qPCR. In vivo, we used the chorioallantoic membrane model (CAM) and characterized effects of Stattic on tumour weight and KI67 expression. RESULTS: All cell lines expressed total STAT3. Treatment of cells with Stattic resulted in a decrease in cell viability in vitro in all cell lines. The combination index of Stattic with 4 different chemotherapeutic agents revealed additive effects on cell growth in some cell lines. Dephosphorylation of STAT3 occurred only in high doses of Stattic and did not correlate with therapy response. Treatment with low dose Stattic regulated subcellular localisation and expression levels of STAT3 downstream targets. In vivo, treatment of tumour xenografts resulted in a significantly reduced tumour weight and KI67 expression. CONCLUSIONS: Our preclinical data demonstrates that the JAK-STAT pathway is a promising molecular target in the treatment of bladder cancer. Further studies are needed to understand the molecular mechanism in detail.
Transcription factor STAT3 is a potential therapeutic target in bladder cancer Eur Urol Suppl 2016;15(3);e926
Print! Print!
Schmid S.C., Yousef A., Sathe A., Horn T., Maurer T., Retz M., Gschwend J.E., Holm P.S., Nawroth R. Technische Universität München, Dept. of Urology, Munich, Germany INTRODUCTION & OBJECTIVES: STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor implicated in cell growth, cell cycle and apoptosis. We analysed the potential of STAT3 as therapeutic target in bladder cancer, using the selective STAT3Inhibitor Stattic. MATERIAL & METHODS: We assessed the effect of Stattic on cell viability in vitro in 20 bladder cancer cell lines. The combination index for combination therapy with cisplatin, gemcitabine, paclitaxel or docetaxel was performed. Immunoblotting and immunofluorescence was used to determine protein expression, phosphorylation and subcellular localization of selected proteins (STAT3, Cyclin D1). Expression of downstream targets was analysed using qPCR. In vivo, we used the chorioallantoic membrane model (CAM) and characterized effects of Stattic on tumour weight and KI67 expression. RESULTS: All cell lines expressed total STAT3. Treatment of cells with Stattic resulted in a decrease in cell viability in vitro in all cell lines. The combination index of Stattic with 4 different chemotherapeutic agents revealed additive effects on cell growth in some cell lines. Dephosphorylation of STAT3 occurred only in high doses of Stattic and did not correlate with therapy response. Treatment with low dose Stattic regulated subcellular localisation and expression levels of STAT3 downstream targets. In vivo, treatment of tumour xenografts resulted in a significantly reduced tumour weight and KI67 expression. CONCLUSIONS: Our preclinical data demonstrates that the JAK-STAT pathway is a promising molecular target in the treatment of bladder cancer. Further studies are needed to understand the molecular mechanism in detail.