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Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells
Major contributors to atherosclerosis are oxidative damage and endoplasmic reticulum (ER) stress-induced apoptosis; both of which can be diminished by the anti-oxidative protein paraoxonase-2 (PON2). ER stress is also relevant to cancer and associated with anti-cancer treatment resistance. Hence, we...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077287/ https://www.ncbi.nlm.nih.gov/pubmed/21368884 http://dx.doi.org/10.1038/cddis.2010.91 |
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author | Witte, I Altenhöfer, S Wilgenbus, P Amort, J Clement, A M Pautz, A Li, H Förstermann, U Horke, S |
author_facet | Witte, I Altenhöfer, S Wilgenbus, P Amort, J Clement, A M Pautz, A Li, H Förstermann, U Horke, S |
author_sort | Witte, I |
collection | PubMed |
description | Major contributors to atherosclerosis are oxidative damage and endoplasmic reticulum (ER) stress-induced apoptosis; both of which can be diminished by the anti-oxidative protein paraoxonase-2 (PON2). ER stress is also relevant to cancer and associated with anti-cancer treatment resistance. Hence, we addressed, for the first time, whether PON2 contributes to tumorigenesis and apoptotic escape. Intriguingly, we found that several human tumors upregulated PON2 and such overexpression provided resistance to different chemotherapeutics (imatinib, doxorubicine, staurosporine, or actinomycin) in cell culture models. This was reversed after PON2 knock-down. Remarkably, just deficiency of PON2 caused apoptosis of selective tumor cells per se, demonstrating a previously unanticipated oncogenic function. We found a dual mechanistic role. During ER stress, high PON2 levels lowered redox-triggered induction of pro-apoptotic CHOP particularly via the JNK pathway, which prevented mitochondrial cell death signaling. Apart from CHOP, PON2 also diminished intrinsic apoptosis as it prevented mitochondrial superoxide formation, cardiolipin peroxidation, cytochrome c release, and caspase activation. Ligand-stimulated apoptosis by TRAIL or TNFα remained unchanged. Finally, PON2 knock-down caused vast reactive oxygen species formation and stimulated JNK-triggered CHOP expression, but inhibition of JNK signaling did not prevent cell death, demonstrating the pleiotropic, dominating anti-oxidative effect of PON2. Therefore, targeting redox balance is powerful to induce selective tumor cell death and proposes PON2 as new putative anti-tumor candidate. |
format | Text |
id | pubmed-3077287 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-30772872011-04-18 Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells Witte, I Altenhöfer, S Wilgenbus, P Amort, J Clement, A M Pautz, A Li, H Förstermann, U Horke, S Cell Death Dis Original Article Major contributors to atherosclerosis are oxidative damage and endoplasmic reticulum (ER) stress-induced apoptosis; both of which can be diminished by the anti-oxidative protein paraoxonase-2 (PON2). ER stress is also relevant to cancer and associated with anti-cancer treatment resistance. Hence, we addressed, for the first time, whether PON2 contributes to tumorigenesis and apoptotic escape. Intriguingly, we found that several human tumors upregulated PON2 and such overexpression provided resistance to different chemotherapeutics (imatinib, doxorubicine, staurosporine, or actinomycin) in cell culture models. This was reversed after PON2 knock-down. Remarkably, just deficiency of PON2 caused apoptosis of selective tumor cells per se, demonstrating a previously unanticipated oncogenic function. We found a dual mechanistic role. During ER stress, high PON2 levels lowered redox-triggered induction of pro-apoptotic CHOP particularly via the JNK pathway, which prevented mitochondrial cell death signaling. Apart from CHOP, PON2 also diminished intrinsic apoptosis as it prevented mitochondrial superoxide formation, cardiolipin peroxidation, cytochrome c release, and caspase activation. Ligand-stimulated apoptosis by TRAIL or TNFα remained unchanged. Finally, PON2 knock-down caused vast reactive oxygen species formation and stimulated JNK-triggered CHOP expression, but inhibition of JNK signaling did not prevent cell death, demonstrating the pleiotropic, dominating anti-oxidative effect of PON2. Therefore, targeting redox balance is powerful to induce selective tumor cell death and proposes PON2 as new putative anti-tumor candidate. Nature Publishing Group 2011-01 2011-01-13 /pmc/articles/PMC3077287/ /pubmed/21368884 http://dx.doi.org/10.1038/cddis.2010.91 Text en Copyright © 2011 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Witte, I Altenhöfer, S Wilgenbus, P Amort, J Clement, A M Pautz, A Li, H Förstermann, U Horke, S Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells |
title | Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells |
title_full | Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells |
title_fullStr | Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells |
title_full_unstemmed | Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells |
title_short | Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells |
title_sort | beyond reduction of atherosclerosis: pon2 provides apoptosis resistance and stabilizes tumor cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077287/ https://www.ncbi.nlm.nih.gov/pubmed/21368884 http://dx.doi.org/10.1038/cddis.2010.91 |
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