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Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching
BACKGROUND: The arachidonic acid metabolite 12(S)-HETE is suspected to enhance metastatic spread by inducing cancer cell- and lymph endothelial cell (LEC) motility. However, the molecular mechanisms leading to 12(S)-HETE-triggered cell migration are still elusive. METHODS: To delineate the signallin...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973159/ https://www.ncbi.nlm.nih.gov/pubmed/27362730 http://dx.doi.org/10.1038/bjc.2016.201 |
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author | Nguyen, Chi Huu Stadler, Serena Brenner, Stefan Huttary, Nicole Krieger, Sigurd Jäger, Walter Dolznig, Helmut Krupitza, Georg |
author_facet | Nguyen, Chi Huu Stadler, Serena Brenner, Stefan Huttary, Nicole Krieger, Sigurd Jäger, Walter Dolznig, Helmut Krupitza, Georg |
author_sort | Nguyen, Chi Huu |
collection | PubMed |
description | BACKGROUND: The arachidonic acid metabolite 12(S)-HETE is suspected to enhance metastatic spread by inducing cancer cell- and lymph endothelial cell (LEC) motility. However, the molecular mechanisms leading to 12(S)-HETE-triggered cell migration are still elusive. METHODS: To delineate the signalling pathways involved in 12(S)-HETE-mediated migration, inhibitors against RHO and ROCK, and specific siRNAs downregulating 12(S)-HETE receptor (12-HETER) and myosin light chain 2 (MLC2) were used. The breaching of the endothelial barrier was investigated by an assay measuring tumour spheroid-triggered ‘circular chemorepellent-induced defects' (CCIDs), and respective signal transduction was elucidated by western blotting. RESULTS: We provide evidence that 12(S)-HETE phosphorylated (and activated) MLC2, which regulates actin/myosin-based contraction. MLC2 activation was found to be essential for LEC retraction and CCID formation. Furthermore, we show that 12(S)-HETE activated a 12-HETER–RHO–ROCK–MYPT signalling cascade to induce MLC2 function. CONCLUSIONS: Signalling via this pathway is described for this metabolite for the first time. This may provide potential targets for the intervention of metastatic colonisation. |
format | Online Article Text |
id | pubmed-4973159 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49731592017-07-26 Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching Nguyen, Chi Huu Stadler, Serena Brenner, Stefan Huttary, Nicole Krieger, Sigurd Jäger, Walter Dolznig, Helmut Krupitza, Georg Br J Cancer Molecular Diagnostics BACKGROUND: The arachidonic acid metabolite 12(S)-HETE is suspected to enhance metastatic spread by inducing cancer cell- and lymph endothelial cell (LEC) motility. However, the molecular mechanisms leading to 12(S)-HETE-triggered cell migration are still elusive. METHODS: To delineate the signalling pathways involved in 12(S)-HETE-mediated migration, inhibitors against RHO and ROCK, and specific siRNAs downregulating 12(S)-HETE receptor (12-HETER) and myosin light chain 2 (MLC2) were used. The breaching of the endothelial barrier was investigated by an assay measuring tumour spheroid-triggered ‘circular chemorepellent-induced defects' (CCIDs), and respective signal transduction was elucidated by western blotting. RESULTS: We provide evidence that 12(S)-HETE phosphorylated (and activated) MLC2, which regulates actin/myosin-based contraction. MLC2 activation was found to be essential for LEC retraction and CCID formation. Furthermore, we show that 12(S)-HETE activated a 12-HETER–RHO–ROCK–MYPT signalling cascade to induce MLC2 function. CONCLUSIONS: Signalling via this pathway is described for this metabolite for the first time. This may provide potential targets for the intervention of metastatic colonisation. Nature Publishing Group 2016-07-26 2016-06-30 /pmc/articles/PMC4973159/ /pubmed/27362730 http://dx.doi.org/10.1038/bjc.2016.201 Text en Copyright © 2016 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Molecular Diagnostics Nguyen, Chi Huu Stadler, Serena Brenner, Stefan Huttary, Nicole Krieger, Sigurd Jäger, Walter Dolznig, Helmut Krupitza, Georg Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching |
title | Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching |
title_full | Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching |
title_fullStr | Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching |
title_full_unstemmed | Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching |
title_short | Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching |
title_sort | cancer cell-derived 12(s)-hete signals via 12-hete receptor, rho, rock and mlc2 to induce lymph endothelial barrier breaching |
topic | Molecular Diagnostics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973159/ https://www.ncbi.nlm.nih.gov/pubmed/27362730 http://dx.doi.org/10.1038/bjc.2016.201 |
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