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PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma
Refractoriness of glioblastoma multiforme (GBM) to current treatment paradigms has necessitated identification of new targets to better the existing therapeutic strategies. One such target is peroxisome proliferator-activated receptor gamma (PPARγ) – a transcription factor involved in regulation of...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979534/ https://www.ncbi.nlm.nih.gov/pubmed/27551468 http://dx.doi.org/10.1038/cddiscovery.2015.38 |
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author | Chatterjee, A Mondal, P Ghosh, S Mehta, VS Sen, E |
author_facet | Chatterjee, A Mondal, P Ghosh, S Mehta, VS Sen, E |
author_sort | Chatterjee, A |
collection | PubMed |
description | Refractoriness of glioblastoma multiforme (GBM) to current treatment paradigms has necessitated identification of new targets to better the existing therapeutic strategies. One such target is peroxisome proliferator-activated receptor gamma (PPARγ) – a transcription factor involved in regulation of lipid metabolism and inflammation. Expression of PPARγ, a known regulator of cell death-inducing DFFA-like effector (CIDEA), is modulated by hypoxia inducible factor (HIF-1α). While the involvement of CIDEA in lipid metabolism is known, its role in malignancies remains largely unknown. An elevated PPARγ and low CIDEA level was observed in GBM tumors as compared with surrounding non-neoplastic tissue. As reciprocal relation exists between PPAR and HIF-1α: and as HIF-1α is a key component in glioma progression, their role in regulating CIDEA expression in glioblastoma was investigated. Although HIF-1α inhibition had no effect on CIDEA expression, pharmacological inhibition of PPARγ elevated CIDEA levels. PPARγ mediated upregulation of CIDEA was accompanied by decreased recruitment of NFκB and SP1 to their predicted binding sites on CIDEA promoter. Ectopic expression of CIDEA triggered apoptosis, activated JNK, decreased HIF-1α activation and increased PPARγ levels in glioma cells. While CIDEA overexpression induced actin cytoskeletal disruption, cell cycle arrest, release of pro-inflammatory cytokine IL-6 in a JNK-dependent manner; CIDEA mediated apoptotic cell death, decreased STAT3 phosphorylation and increased p53 acetylation was JNK independent. This study highlights for the first time the existence of (i) PPARγ-CIDEA regulatory loop in glioma and (ii) novel function of CIDEA as regulator of glioma cell survival. |
format | Online Article Text |
id | pubmed-4979534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49795342016-08-22 PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma Chatterjee, A Mondal, P Ghosh, S Mehta, VS Sen, E Cell Death Discov Article Refractoriness of glioblastoma multiforme (GBM) to current treatment paradigms has necessitated identification of new targets to better the existing therapeutic strategies. One such target is peroxisome proliferator-activated receptor gamma (PPARγ) – a transcription factor involved in regulation of lipid metabolism and inflammation. Expression of PPARγ, a known regulator of cell death-inducing DFFA-like effector (CIDEA), is modulated by hypoxia inducible factor (HIF-1α). While the involvement of CIDEA in lipid metabolism is known, its role in malignancies remains largely unknown. An elevated PPARγ and low CIDEA level was observed in GBM tumors as compared with surrounding non-neoplastic tissue. As reciprocal relation exists between PPAR and HIF-1α: and as HIF-1α is a key component in glioma progression, their role in regulating CIDEA expression in glioblastoma was investigated. Although HIF-1α inhibition had no effect on CIDEA expression, pharmacological inhibition of PPARγ elevated CIDEA levels. PPARγ mediated upregulation of CIDEA was accompanied by decreased recruitment of NFκB and SP1 to their predicted binding sites on CIDEA promoter. Ectopic expression of CIDEA triggered apoptosis, activated JNK, decreased HIF-1α activation and increased PPARγ levels in glioma cells. While CIDEA overexpression induced actin cytoskeletal disruption, cell cycle arrest, release of pro-inflammatory cytokine IL-6 in a JNK-dependent manner; CIDEA mediated apoptotic cell death, decreased STAT3 phosphorylation and increased p53 acetylation was JNK independent. This study highlights for the first time the existence of (i) PPARγ-CIDEA regulatory loop in glioma and (ii) novel function of CIDEA as regulator of glioma cell survival. Nature Publishing Group 2015-11-23 /pmc/articles/PMC4979534/ /pubmed/27551468 http://dx.doi.org/10.1038/cddiscovery.2015.38 Text en Copyright © 2015 Cell Death Differentiation Association http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Chatterjee, A Mondal, P Ghosh, S Mehta, VS Sen, E PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma |
title | PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma |
title_full | PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma |
title_fullStr | PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma |
title_full_unstemmed | PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma |
title_short | PPARγ regulated CIDEA affects pro-apoptotic responses in glioblastoma |
title_sort | pparγ regulated cidea affects pro-apoptotic responses in glioblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979534/ https://www.ncbi.nlm.nih.gov/pubmed/27551468 http://dx.doi.org/10.1038/cddiscovery.2015.38 |
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