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Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling
Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210471/ https://www.ncbi.nlm.nih.gov/pubmed/30274176 http://dx.doi.org/10.3390/cancers10100363 |
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author | Piwowarczyk, Katarzyna Kwiecień, Edyta Sośniak, Justyna Zimoląg, Eliza Guzik, Emiliana Sroka, Jolanta Madeja, Zbigniew Czyż, Jarosław |
author_facet | Piwowarczyk, Katarzyna Kwiecień, Edyta Sośniak, Justyna Zimoląg, Eliza Guzik, Emiliana Sroka, Jolanta Madeja, Zbigniew Czyż, Jarosław |
author_sort | Piwowarczyk, Katarzyna |
collection | PubMed |
description | Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways and to quantify the effect of fenofibrate (FF) on their activity. A549 cells induced the disruption and local activation of endothelial continuum. These events were accompanied by epidermal growth factor (EGF) up-regulation in endothelial cells. Impaired A549 diapedesis and HUVEC activation were seen upon the chemical inhibition of connexin(Cx)43 functions, EGF/ERK1/2-dependent signaling, and RhoA/Rac1 activity. A total of 25 μM FF exerted corresponding effects on Cx43-mediated gap junctional coupling, EGF production, and ERK1/2 activation in HUVEC/A549 co-cultures. It also directly augmented endothelial barrier function via the interference with focal adhesion kinase (FAK)/RhoA/Rac1-regulated endothelial cell adhesion/contractility/motility and prompted the selective transmigration of epithelioid A549 cells. N-acetyl-L-cysteine abrogated FF effects on HUVEC activation, suggesting the involvement of PPARα-independent mechanism(s) in its action. Our data identify a novel Cx43/EGF/ERK1/2/FAK/RhoA/Rac1-dependent signaling axis, which determines the efficiency of lung cancer cell diapedesis. FF interferes with its activity and reduces the susceptibility of endothelial cells to A549 stimuli. These findings provide the rationale for the implementation of FF in the therapy of malignant lung cancers. |
format | Online Article Text |
id | pubmed-6210471 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62104712018-11-02 Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling Piwowarczyk, Katarzyna Kwiecień, Edyta Sośniak, Justyna Zimoląg, Eliza Guzik, Emiliana Sroka, Jolanta Madeja, Zbigniew Czyż, Jarosław Cancers (Basel) Article Extravasation of circulating cancer cells is regulated by the intercellular/intracellular signaling pathways that locally impair the endothelial barrier function. Co-cultures of human umbilical vein endothelial cells (HUVECs) with lung adenocarcinoma A549 cells enabled us to identify these pathways and to quantify the effect of fenofibrate (FF) on their activity. A549 cells induced the disruption and local activation of endothelial continuum. These events were accompanied by epidermal growth factor (EGF) up-regulation in endothelial cells. Impaired A549 diapedesis and HUVEC activation were seen upon the chemical inhibition of connexin(Cx)43 functions, EGF/ERK1/2-dependent signaling, and RhoA/Rac1 activity. A total of 25 μM FF exerted corresponding effects on Cx43-mediated gap junctional coupling, EGF production, and ERK1/2 activation in HUVEC/A549 co-cultures. It also directly augmented endothelial barrier function via the interference with focal adhesion kinase (FAK)/RhoA/Rac1-regulated endothelial cell adhesion/contractility/motility and prompted the selective transmigration of epithelioid A549 cells. N-acetyl-L-cysteine abrogated FF effects on HUVEC activation, suggesting the involvement of PPARα-independent mechanism(s) in its action. Our data identify a novel Cx43/EGF/ERK1/2/FAK/RhoA/Rac1-dependent signaling axis, which determines the efficiency of lung cancer cell diapedesis. FF interferes with its activity and reduces the susceptibility of endothelial cells to A549 stimuli. These findings provide the rationale for the implementation of FF in the therapy of malignant lung cancers. MDPI 2018-09-28 /pmc/articles/PMC6210471/ /pubmed/30274176 http://dx.doi.org/10.3390/cancers10100363 Text en © 2018 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 Piwowarczyk, Katarzyna Kwiecień, Edyta Sośniak, Justyna Zimoląg, Eliza Guzik, Emiliana Sroka, Jolanta Madeja, Zbigniew Czyż, Jarosław Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling |
title | Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling |
title_full | Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling |
title_fullStr | Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling |
title_full_unstemmed | Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling |
title_short | Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling |
title_sort | fenofibrate interferes with the diapedesis of lung adenocarcinoma cells through the interference with cx43/egf-dependent intercellular signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210471/ https://www.ncbi.nlm.nih.gov/pubmed/30274176 http://dx.doi.org/10.3390/cancers10100363 |
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