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The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone

The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harbo...

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Autores principales: Eigner, Karin, Filik, Yüksel, Mark, Florian, Schütz, Birgit, Klambauer, Günter, Moriggl, Richard, Hengstschläger, Markus, Stangl, Herbert, Mikula, Mario, Röhrl, Clemens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727496/
https://www.ncbi.nlm.nih.gov/pubmed/29235576
http://dx.doi.org/10.1038/s41598-017-17888-9
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author Eigner, Karin
Filik, Yüksel
Mark, Florian
Schütz, Birgit
Klambauer, Günter
Moriggl, Richard
Hengstschläger, Markus
Stangl, Herbert
Mikula, Mario
Röhrl, Clemens
author_facet Eigner, Karin
Filik, Yüksel
Mark, Florian
Schütz, Birgit
Klambauer, Günter
Moriggl, Richard
Hengstschläger, Markus
Stangl, Herbert
Mikula, Mario
Röhrl, Clemens
author_sort Eigner, Karin
collection PubMed
description The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAF(V600E)-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the chemical chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF-receptor signalling axis and promotes melanoma progression. Hence, the development of potent chemical chaperones to antagonize the UPR might be a therapeutic approach to target melanoma.
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spelling pubmed-57274962017-12-18 The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone Eigner, Karin Filik, Yüksel Mark, Florian Schütz, Birgit Klambauer, Günter Moriggl, Richard Hengstschläger, Markus Stangl, Herbert Mikula, Mario Röhrl, Clemens Sci Rep Article The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAF(V600E)-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the chemical chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF-receptor signalling axis and promotes melanoma progression. Hence, the development of potent chemical chaperones to antagonize the UPR might be a therapeutic approach to target melanoma. Nature Publishing Group UK 2017-12-13 /pmc/articles/PMC5727496/ /pubmed/29235576 http://dx.doi.org/10.1038/s41598-017-17888-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Eigner, Karin
Filik, Yüksel
Mark, Florian
Schütz, Birgit
Klambauer, Günter
Moriggl, Richard
Hengstschläger, Markus
Stangl, Herbert
Mikula, Mario
Röhrl, Clemens
The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone
title The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone
title_full The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone
title_fullStr The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone
title_full_unstemmed The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone
title_short The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone
title_sort unfolded protein response impacts melanoma progression by enhancing fgf expression and can be antagonized by a chemical chaperone
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727496/
https://www.ncbi.nlm.nih.gov/pubmed/29235576
http://dx.doi.org/10.1038/s41598-017-17888-9
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