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Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway
Malignant gliomas are highly proliferative and invasive neoplasms where total surgical resection is often impossible and effective local radiation therapy difficult. Consequently, there is a need to develop a greater understanding of the molecular events driving invasion and to identify novel treatm...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253441/ https://www.ncbi.nlm.nih.gov/pubmed/25237832 |
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author | Park, Jun-Bum Agnihotri, Sameer Golbourn, Brian Bertrand, Kelsey C. Luck, Amanda Sabha, Nesrin Smith, Christian A. Byron, Sara Zadeh, Gelareh Croul, Sidney Berens, Michael Rutka, James T. |
author_facet | Park, Jun-Bum Agnihotri, Sameer Golbourn, Brian Bertrand, Kelsey C. Luck, Amanda Sabha, Nesrin Smith, Christian A. Byron, Sara Zadeh, Gelareh Croul, Sidney Berens, Michael Rutka, James T. |
author_sort | Park, Jun-Bum |
collection | PubMed |
description | Malignant gliomas are highly proliferative and invasive neoplasms where total surgical resection is often impossible and effective local radiation therapy difficult. Consequently, there is a need to develop a greater understanding of the molecular events driving invasion and to identify novel treatment targets. Using microarray analysis comparing normal brain samples and mesenchymal glioblastoma multiforme (GBM), we identified over 140 significant genes involved in cell migration and invasion. The cofilin (CFL) pathway, which disassembles actin filaments, was highly up-regulated compared to normal brain. Up-regulation of LIM domain kinase 1 and 2 (LIMK1/2), that phosphorylates and inactivates cofilin, was confirmed in an additional independent data set comparing normal brain to GBM. We identified and utilized two small molecule inhibitors BMS-5 and Cucurbitacin I directed against the cofilin regulating kinases, LIMK1 and LIMK2, to target this pathway. Significant decreases in cell viability were observed in glioma cells treated with BMS-5 and Cucurbitacin I, while no cytotoxic effects were seen in normal astrocytes that lack LIMK. BMS-5 and Cucurbitacin I promoted increased adhesion in GBM cells, and decreased migration and invasion. Collectively, these data suggest that use of LIMK inhibitors may provide a novel way to target the invasive machinery in GBM. |
format | Online Article Text |
id | pubmed-4253441 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-42534412014-12-03 Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway Park, Jun-Bum Agnihotri, Sameer Golbourn, Brian Bertrand, Kelsey C. Luck, Amanda Sabha, Nesrin Smith, Christian A. Byron, Sara Zadeh, Gelareh Croul, Sidney Berens, Michael Rutka, James T. Oncotarget Research Paper Malignant gliomas are highly proliferative and invasive neoplasms where total surgical resection is often impossible and effective local radiation therapy difficult. Consequently, there is a need to develop a greater understanding of the molecular events driving invasion and to identify novel treatment targets. Using microarray analysis comparing normal brain samples and mesenchymal glioblastoma multiforme (GBM), we identified over 140 significant genes involved in cell migration and invasion. The cofilin (CFL) pathway, which disassembles actin filaments, was highly up-regulated compared to normal brain. Up-regulation of LIM domain kinase 1 and 2 (LIMK1/2), that phosphorylates and inactivates cofilin, was confirmed in an additional independent data set comparing normal brain to GBM. We identified and utilized two small molecule inhibitors BMS-5 and Cucurbitacin I directed against the cofilin regulating kinases, LIMK1 and LIMK2, to target this pathway. Significant decreases in cell viability were observed in glioma cells treated with BMS-5 and Cucurbitacin I, while no cytotoxic effects were seen in normal astrocytes that lack LIMK. BMS-5 and Cucurbitacin I promoted increased adhesion in GBM cells, and decreased migration and invasion. Collectively, these data suggest that use of LIMK inhibitors may provide a novel way to target the invasive machinery in GBM. Impact Journals LLC 2014-09-05 /pmc/articles/PMC4253441/ /pubmed/25237832 Text en Copyright: © 2014 Park et al. http://creativecommons.org/licenses/by/2.5/ 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 credited |
spellingShingle | Research Paper Park, Jun-Bum Agnihotri, Sameer Golbourn, Brian Bertrand, Kelsey C. Luck, Amanda Sabha, Nesrin Smith, Christian A. Byron, Sara Zadeh, Gelareh Croul, Sidney Berens, Michael Rutka, James T. Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway |
title | Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway |
title_full | Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway |
title_fullStr | Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway |
title_full_unstemmed | Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway |
title_short | Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway |
title_sort | transcriptional profiling of gbm invasion genes identifies effective inhibitors of the lim kinase-cofilin pathway |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253441/ https://www.ncbi.nlm.nih.gov/pubmed/25237832 |
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