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Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis

BACKGROUND: We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Moreover, ENO1 silencing in PDA cells induces oxidative stress, senescence and pro...

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Autores principales: Principe, Moitza, Borgoni, Simone, Cascione, Mariafrancesca, Chattaragada, Michelle Samuel, Ferri-Borgogno, Sammy, Capello, Michela, Bulfamante, Sara, Chapelle, Jennifer, Di Modugno, Francesca, Defilippi, Paola, Nisticò, Paola, Cappello, Paola, Riganti, Chiara, Leporatti, Stefano, Novelli, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237223/
https://www.ncbi.nlm.nih.gov/pubmed/28086938
http://dx.doi.org/10.1186/s13045-016-0385-8
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author Principe, Moitza
Borgoni, Simone
Cascione, Mariafrancesca
Chattaragada, Michelle Samuel
Ferri-Borgogno, Sammy
Capello, Michela
Bulfamante, Sara
Chapelle, Jennifer
Di Modugno, Francesca
Defilippi, Paola
Nisticò, Paola
Cappello, Paola
Riganti, Chiara
Leporatti, Stefano
Novelli, Francesco
author_facet Principe, Moitza
Borgoni, Simone
Cascione, Mariafrancesca
Chattaragada, Michelle Samuel
Ferri-Borgogno, Sammy
Capello, Michela
Bulfamante, Sara
Chapelle, Jennifer
Di Modugno, Francesca
Defilippi, Paola
Nisticò, Paola
Cappello, Paola
Riganti, Chiara
Leporatti, Stefano
Novelli, Francesco
author_sort Principe, Moitza
collection PubMed
description BACKGROUND: We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Moreover, ENO1 silencing in PDA cells induces oxidative stress, senescence and profoundly modifies PDA cell metabolism. Although anti-ENO1 antibody inhibits PDA cell migration and invasion, little is known about the role of ENO1 in regulating cell-cell and cell-matrix contacts. We therefore investigated the effect of ENO1 silencing on the modulation of cell morphology, adhesion to matrix substrates, cell invasiveness, and metastatic ability. METHODS: The membrane and cytoskeleton modifications that occurred in ENO1-silenced (shENO1) PDA cells were investigated by a combination of confocal microscopy and atomic force microscopy (AFM). The effect of ENO1 silencing was then evaluated by phenotypic and functional experiments to identify the role of ENO1 in adhesion, migration, and invasion, as well as in senescence and apoptosis. The experimental results were then validated in a mouse model. RESULTS: We observed a significant increase in the roughness of the cell membrane due to ENO1 silencing, a feature associated with an impaired ability to migrate and invade, along with a significant downregulation of proteins involved in cell-cell and cell-matrix adhesion, including alpha v/beta 3 integrin in shENO1 PDA cells. These changes impaired the ability of shENO1 cells to adhere to Collagen I and IV and Fibronectin and caused an increase in RGD-independent adhesion to vitronectin (VN) via urokinase plasminogen activator receptor (uPAR). Binding of uPAR to VN triggers integrin-mediated signals, which result in ERK1-2 and RAC activation, accumulation of ROS, and senescence. In shENO1 cancer cells, the use of an anti-uPAR antibody caused significant reduction of ROS production and senescence. Overall, a decrease of in vitro and in vivo cell migration and invasion of shENO1 PDA cells was observed. CONCLUSION: These data demonstrate that ENO1 promotes PDA survival, migration, and metastasis through cooperation with integrins and uPAR. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-016-0385-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-52372232017-01-18 Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis Principe, Moitza Borgoni, Simone Cascione, Mariafrancesca Chattaragada, Michelle Samuel Ferri-Borgogno, Sammy Capello, Michela Bulfamante, Sara Chapelle, Jennifer Di Modugno, Francesca Defilippi, Paola Nisticò, Paola Cappello, Paola Riganti, Chiara Leporatti, Stefano Novelli, Francesco J Hematol Oncol Research BACKGROUND: We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Moreover, ENO1 silencing in PDA cells induces oxidative stress, senescence and profoundly modifies PDA cell metabolism. Although anti-ENO1 antibody inhibits PDA cell migration and invasion, little is known about the role of ENO1 in regulating cell-cell and cell-matrix contacts. We therefore investigated the effect of ENO1 silencing on the modulation of cell morphology, adhesion to matrix substrates, cell invasiveness, and metastatic ability. METHODS: The membrane and cytoskeleton modifications that occurred in ENO1-silenced (shENO1) PDA cells were investigated by a combination of confocal microscopy and atomic force microscopy (AFM). The effect of ENO1 silencing was then evaluated by phenotypic and functional experiments to identify the role of ENO1 in adhesion, migration, and invasion, as well as in senescence and apoptosis. The experimental results were then validated in a mouse model. RESULTS: We observed a significant increase in the roughness of the cell membrane due to ENO1 silencing, a feature associated with an impaired ability to migrate and invade, along with a significant downregulation of proteins involved in cell-cell and cell-matrix adhesion, including alpha v/beta 3 integrin in shENO1 PDA cells. These changes impaired the ability of shENO1 cells to adhere to Collagen I and IV and Fibronectin and caused an increase in RGD-independent adhesion to vitronectin (VN) via urokinase plasminogen activator receptor (uPAR). Binding of uPAR to VN triggers integrin-mediated signals, which result in ERK1-2 and RAC activation, accumulation of ROS, and senescence. In shENO1 cancer cells, the use of an anti-uPAR antibody caused significant reduction of ROS production and senescence. Overall, a decrease of in vitro and in vivo cell migration and invasion of shENO1 PDA cells was observed. CONCLUSION: These data demonstrate that ENO1 promotes PDA survival, migration, and metastasis through cooperation with integrins and uPAR. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-016-0385-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-01-13 /pmc/articles/PMC5237223/ /pubmed/28086938 http://dx.doi.org/10.1186/s13045-016-0385-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Principe, Moitza
Borgoni, Simone
Cascione, Mariafrancesca
Chattaragada, Michelle Samuel
Ferri-Borgogno, Sammy
Capello, Michela
Bulfamante, Sara
Chapelle, Jennifer
Di Modugno, Francesca
Defilippi, Paola
Nisticò, Paola
Cappello, Paola
Riganti, Chiara
Leporatti, Stefano
Novelli, Francesco
Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis
title Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis
title_full Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis
title_fullStr Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis
title_full_unstemmed Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis
title_short Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis
title_sort alpha-enolase (eno1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237223/
https://www.ncbi.nlm.nih.gov/pubmed/28086938
http://dx.doi.org/10.1186/s13045-016-0385-8
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