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S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer
Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216974/ https://www.ncbi.nlm.nih.gov/pubmed/22110663 http://dx.doi.org/10.1371/journal.pone.0027509 |
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author | Nawroth, Roman Stellwagen, Florian Schulz, Wolfgang A. Stoehr, Robert Hartmann, Arndt Krause, Bernd J. Gschwend, Juergen E. Retz, Margitta |
author_facet | Nawroth, Roman Stellwagen, Florian Schulz, Wolfgang A. Stoehr, Robert Hartmann, Arndt Krause, Bernd J. Gschwend, Juergen E. Retz, Margitta |
author_sort | Nawroth, Roman |
collection | PubMed |
description | Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK. |
format | Online Article Text |
id | pubmed-3216974 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32169742011-11-21 S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer Nawroth, Roman Stellwagen, Florian Schulz, Wolfgang A. Stoehr, Robert Hartmann, Arndt Krause, Bernd J. Gschwend, Juergen E. Retz, Margitta PLoS One Research Article Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK. Public Library of Science 2011-11-15 /pmc/articles/PMC3216974/ /pubmed/22110663 http://dx.doi.org/10.1371/journal.pone.0027509 Text en Nawroth et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Nawroth, Roman Stellwagen, Florian Schulz, Wolfgang A. Stoehr, Robert Hartmann, Arndt Krause, Bernd J. Gschwend, Juergen E. Retz, Margitta S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer |
title | S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer |
title_full | S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer |
title_fullStr | S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer |
title_full_unstemmed | S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer |
title_short | S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer |
title_sort | s6k1 and 4e-bp1 are independent regulated and control cellular growth in bladder cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216974/ https://www.ncbi.nlm.nih.gov/pubmed/22110663 http://dx.doi.org/10.1371/journal.pone.0027509 |
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