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Effects of PPARα inhibition in head and neck paraganglioma cells
Head and neck paragangliomas (HNPGLs) are rare tumors that may cause important morbidity, because of their tendency to infiltrate the skull base. At present, surgery is the only therapeutic option, but radical removal may be difficult or impossible. Thus, effective targets and molecules for HNPGL tr...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464765/ https://www.ncbi.nlm.nih.gov/pubmed/28594934 http://dx.doi.org/10.1371/journal.pone.0178995 |
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author | Florio, Rosalba De Lellis, Laura di Giacomo, Viviana Di Marcantonio, Maria Carmela Cristiano, Loredana Basile, Mariangela Verginelli, Fabio Verzilli, Delfina Ammazzalorso, Alessandra Prasad, Sampath Chandra Cataldi, Amelia Sanna, Mario Cimini, Annamaria Mariani-Costantini, Renato Mincione, Gabriella Cama, Alessandro |
author_facet | Florio, Rosalba De Lellis, Laura di Giacomo, Viviana Di Marcantonio, Maria Carmela Cristiano, Loredana Basile, Mariangela Verginelli, Fabio Verzilli, Delfina Ammazzalorso, Alessandra Prasad, Sampath Chandra Cataldi, Amelia Sanna, Mario Cimini, Annamaria Mariani-Costantini, Renato Mincione, Gabriella Cama, Alessandro |
author_sort | Florio, Rosalba |
collection | PubMed |
description | Head and neck paragangliomas (HNPGLs) are rare tumors that may cause important morbidity, because of their tendency to infiltrate the skull base. At present, surgery is the only therapeutic option, but radical removal may be difficult or impossible. Thus, effective targets and molecules for HNPGL treatment need to be identified. However, the lack of cellular models for this rare tumor hampers this task. PPARα receptor activation was reported in several tumors and this receptor appears to be a promising therapeutic target in different malignancies. Considering that the role of PPARα in HNPGLs was never studied before, we analyzed the potential of modulating PPARα in a unique model of HNPGL cells. We observed an intense immunoreactivity for PPARα in HNPGL tumors, suggesting that this receptor has an important role in HNPGL. A pronounced nuclear expression of PPARα was also confirmed in HNPGL-derived cells. The specific PPARα agonist WY14643 had no effect on HNPGL cell viability, whereas the specific PPARα antagonist GW6471 reduced HNPGL cell viability and growth by inducing cell cycle arrest and caspase-dependent apoptosis. GW6471 treatment was associated with a marked decrease of CDK4, cyclin D3 and cyclin B1 protein expression, along with an increased expression of p21 in HNPGL cells. Moreover, GW6471 drastically impaired clonogenic activity of HNPGL cells, with a less marked effect on cell migration. Notably, the effects of GW6471 on HNPGL cells were associated with the inhibition of the PI3K/GSK3β/β-catenin signaling pathway. In conclusion, the PPARα antagonist GW6471 reduces HNPGL cell viability, interfering with cell cycle and inducing apoptosis. The mechanisms affecting HNPGL cell viability involve repression of the PI3K/GSK3β/β-catenin pathway. Therefore, PPARα could represent a novel therapeutic target for HNPGL. |
format | Online Article Text |
id | pubmed-5464765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54647652017-06-22 Effects of PPARα inhibition in head and neck paraganglioma cells Florio, Rosalba De Lellis, Laura di Giacomo, Viviana Di Marcantonio, Maria Carmela Cristiano, Loredana Basile, Mariangela Verginelli, Fabio Verzilli, Delfina Ammazzalorso, Alessandra Prasad, Sampath Chandra Cataldi, Amelia Sanna, Mario Cimini, Annamaria Mariani-Costantini, Renato Mincione, Gabriella Cama, Alessandro PLoS One Research Article Head and neck paragangliomas (HNPGLs) are rare tumors that may cause important morbidity, because of their tendency to infiltrate the skull base. At present, surgery is the only therapeutic option, but radical removal may be difficult or impossible. Thus, effective targets and molecules for HNPGL treatment need to be identified. However, the lack of cellular models for this rare tumor hampers this task. PPARα receptor activation was reported in several tumors and this receptor appears to be a promising therapeutic target in different malignancies. Considering that the role of PPARα in HNPGLs was never studied before, we analyzed the potential of modulating PPARα in a unique model of HNPGL cells. We observed an intense immunoreactivity for PPARα in HNPGL tumors, suggesting that this receptor has an important role in HNPGL. A pronounced nuclear expression of PPARα was also confirmed in HNPGL-derived cells. The specific PPARα agonist WY14643 had no effect on HNPGL cell viability, whereas the specific PPARα antagonist GW6471 reduced HNPGL cell viability and growth by inducing cell cycle arrest and caspase-dependent apoptosis. GW6471 treatment was associated with a marked decrease of CDK4, cyclin D3 and cyclin B1 protein expression, along with an increased expression of p21 in HNPGL cells. Moreover, GW6471 drastically impaired clonogenic activity of HNPGL cells, with a less marked effect on cell migration. Notably, the effects of GW6471 on HNPGL cells were associated with the inhibition of the PI3K/GSK3β/β-catenin signaling pathway. In conclusion, the PPARα antagonist GW6471 reduces HNPGL cell viability, interfering with cell cycle and inducing apoptosis. The mechanisms affecting HNPGL cell viability involve repression of the PI3K/GSK3β/β-catenin pathway. Therefore, PPARα could represent a novel therapeutic target for HNPGL. Public Library of Science 2017-06-08 /pmc/articles/PMC5464765/ /pubmed/28594934 http://dx.doi.org/10.1371/journal.pone.0178995 Text en © 2017 Florio et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Florio, Rosalba De Lellis, Laura di Giacomo, Viviana Di Marcantonio, Maria Carmela Cristiano, Loredana Basile, Mariangela Verginelli, Fabio Verzilli, Delfina Ammazzalorso, Alessandra Prasad, Sampath Chandra Cataldi, Amelia Sanna, Mario Cimini, Annamaria Mariani-Costantini, Renato Mincione, Gabriella Cama, Alessandro Effects of PPARα inhibition in head and neck paraganglioma cells |
title | Effects of PPARα inhibition in head and neck paraganglioma cells |
title_full | Effects of PPARα inhibition in head and neck paraganglioma cells |
title_fullStr | Effects of PPARα inhibition in head and neck paraganglioma cells |
title_full_unstemmed | Effects of PPARα inhibition in head and neck paraganglioma cells |
title_short | Effects of PPARα inhibition in head and neck paraganglioma cells |
title_sort | effects of pparα inhibition in head and neck paraganglioma cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464765/ https://www.ncbi.nlm.nih.gov/pubmed/28594934 http://dx.doi.org/10.1371/journal.pone.0178995 |
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