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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...

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Autores principales: Nguyen, Chi Huu, Stadler, Serena, Brenner, Stefan, Huttary, Nicole, Krieger, Sigurd, Jäger, Walter, Dolznig, Helmut, Krupitza, Georg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
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.
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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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