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JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress
Hyperproliferating cancer cells produce energy mainly from aerobic glycolysis, which results in elevated ROS levels. Thus aggressive tumors often possess enhanced anti-oxidant capacity that impedes many current anti-cancer therapies. Additionally, in ROS-compromised cancer cells ubiquitin proteasome...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649515/ https://www.ncbi.nlm.nih.gov/pubmed/25341038 http://dx.doi.org/10.1038/cddis.2014.408 |
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author | Kostecka, A Sznarkowska, A Meller, K Acedo, P Shi, Y Mohammad Sakil, H A Kawiak, A Lion, M Królicka, A Wilhelm, M Inga, A Zawacka-Pankau, J |
author_facet | Kostecka, A Sznarkowska, A Meller, K Acedo, P Shi, Y Mohammad Sakil, H A Kawiak, A Lion, M Królicka, A Wilhelm, M Inga, A Zawacka-Pankau, J |
author_sort | Kostecka, A |
collection | PubMed |
description | Hyperproliferating cancer cells produce energy mainly from aerobic glycolysis, which results in elevated ROS levels. Thus aggressive tumors often possess enhanced anti-oxidant capacity that impedes many current anti-cancer therapies. Additionally, in ROS-compromised cancer cells ubiquitin proteasome system (UPS) is often deregulated for timely removal of oxidized proteins, thus enabling cell survival. Taken that UPS maintains the turnover of factors controlling cell cycle and apoptosis – such as p53 or p73, it represents a promising target for pharmaceutical intervention. Enhancing oxidative insult in already ROS-compromised cancer cells appears as an attractive anti-tumor scenario. TAp73 is a bona fide tumor suppressor that drives the chemosensitivity of some cancers to cisplatin or γ-radiation. It is an important drug target in tumors where p53 is lost or mutated. Here we discovered a novel synergistic mechanism leading to potent p73 activation and cancer cell death by oxidative stress and inhibition of 20S proteasomes. Using a small-molecule inhibitor of 20S proteasome and ROS-inducer – withaferin A (WA), we found that WA-induced ROS activates JNK kinase and stabilizes phase II anti-oxidant response effector NF-E2-related transcription factor (NRF2). This results in activation of Nrf2 target – NQO1 (NADPH quinone oxidoreductase), and TAp73 protein stabilization. The observed effect was ablated by the ROS scavenger – NAC. Concurrently, stress-activated JNK phosphorylates TAp73 at multiple serine and threonine residues, which is crucial to ablate TAp73/MDM2 complex and to promote TAp73 transcriptional function and induction of robust apoptosis. Taken together our data demonstrate that ROS insult in combination with the inhibition of 20S proteasome and TAp73 activation endows synthetic lethality in cancer cells. Thus, our results may enable the establishment of a novel pharmacological strategy to exploit the enhanced sensitivity of tumors to elevated ROS and proteasomal stress to kill advanced tumors by pharmacological activation of TAp73 using molecules like WA. |
format | Online Article Text |
id | pubmed-4649515 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46495152015-12-01 JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress Kostecka, A Sznarkowska, A Meller, K Acedo, P Shi, Y Mohammad Sakil, H A Kawiak, A Lion, M Królicka, A Wilhelm, M Inga, A Zawacka-Pankau, J Cell Death Dis Original Article Hyperproliferating cancer cells produce energy mainly from aerobic glycolysis, which results in elevated ROS levels. Thus aggressive tumors often possess enhanced anti-oxidant capacity that impedes many current anti-cancer therapies. Additionally, in ROS-compromised cancer cells ubiquitin proteasome system (UPS) is often deregulated for timely removal of oxidized proteins, thus enabling cell survival. Taken that UPS maintains the turnover of factors controlling cell cycle and apoptosis – such as p53 or p73, it represents a promising target for pharmaceutical intervention. Enhancing oxidative insult in already ROS-compromised cancer cells appears as an attractive anti-tumor scenario. TAp73 is a bona fide tumor suppressor that drives the chemosensitivity of some cancers to cisplatin or γ-radiation. It is an important drug target in tumors where p53 is lost or mutated. Here we discovered a novel synergistic mechanism leading to potent p73 activation and cancer cell death by oxidative stress and inhibition of 20S proteasomes. Using a small-molecule inhibitor of 20S proteasome and ROS-inducer – withaferin A (WA), we found that WA-induced ROS activates JNK kinase and stabilizes phase II anti-oxidant response effector NF-E2-related transcription factor (NRF2). This results in activation of Nrf2 target – NQO1 (NADPH quinone oxidoreductase), and TAp73 protein stabilization. The observed effect was ablated by the ROS scavenger – NAC. Concurrently, stress-activated JNK phosphorylates TAp73 at multiple serine and threonine residues, which is crucial to ablate TAp73/MDM2 complex and to promote TAp73 transcriptional function and induction of robust apoptosis. Taken together our data demonstrate that ROS insult in combination with the inhibition of 20S proteasome and TAp73 activation endows synthetic lethality in cancer cells. Thus, our results may enable the establishment of a novel pharmacological strategy to exploit the enhanced sensitivity of tumors to elevated ROS and proteasomal stress to kill advanced tumors by pharmacological activation of TAp73 using molecules like WA. Nature Publishing Group 2014-10 2014-10-23 /pmc/articles/PMC4649515/ /pubmed/25341038 http://dx.doi.org/10.1038/cddis.2014.408 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/3.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 3.0 Unported 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/3.0/ |
spellingShingle | Original Article Kostecka, A Sznarkowska, A Meller, K Acedo, P Shi, Y Mohammad Sakil, H A Kawiak, A Lion, M Królicka, A Wilhelm, M Inga, A Zawacka-Pankau, J JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress |
title | JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress |
title_full | JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress |
title_fullStr | JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress |
title_full_unstemmed | JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress |
title_short | JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress |
title_sort | jnk–nqo1 axis drives tap73-mediated tumor suppression upon oxidative and proteasomal stress |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649515/ https://www.ncbi.nlm.nih.gov/pubmed/25341038 http://dx.doi.org/10.1038/cddis.2014.408 |
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