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STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy
The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043223/ https://www.ncbi.nlm.nih.gov/pubmed/32046095 http://dx.doi.org/10.3390/ijms21031106 |
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author | Hindupur, Sruthi V. Schmid, Sebastian C. Koch, Jana Annika Youssef, Ahmed Baur, Eva-Maria Wang, Dongbiao Horn, Thomas Slotta-Huspenina, Julia Gschwend, Juergen E. Holm, Per Sonne Nawroth, Roman |
author_facet | Hindupur, Sruthi V. Schmid, Sebastian C. Koch, Jana Annika Youssef, Ahmed Baur, Eva-Maria Wang, Dongbiao Horn, Thomas Slotta-Huspenina, Julia Gschwend, Juergen E. Holm, Per Sonne Nawroth, Roman |
author_sort | Hindupur, Sruthi V. |
collection | PubMed |
description | The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer. |
format | Online Article Text |
id | pubmed-7043223 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70432232020-03-12 STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy Hindupur, Sruthi V. Schmid, Sebastian C. Koch, Jana Annika Youssef, Ahmed Baur, Eva-Maria Wang, Dongbiao Horn, Thomas Slotta-Huspenina, Julia Gschwend, Juergen E. Holm, Per Sonne Nawroth, Roman Int J Mol Sci Article The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer. MDPI 2020-02-07 /pmc/articles/PMC7043223/ /pubmed/32046095 http://dx.doi.org/10.3390/ijms21031106 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hindupur, Sruthi V. Schmid, Sebastian C. Koch, Jana Annika Youssef, Ahmed Baur, Eva-Maria Wang, Dongbiao Horn, Thomas Slotta-Huspenina, Julia Gschwend, Juergen E. Holm, Per Sonne Nawroth, Roman STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy |
title | STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy |
title_full | STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy |
title_fullStr | STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy |
title_full_unstemmed | STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy |
title_short | STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy |
title_sort | stat3/5 inhibitors suppress proliferation in bladder cancer and enhance oncolytic adenovirus therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043223/ https://www.ncbi.nlm.nih.gov/pubmed/32046095 http://dx.doi.org/10.3390/ijms21031106 |
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