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Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation

Senescence is associated with tumor metastasis and chemotherapy resistance, yet the mechanisms remain elusive. Here, it is identified that nasopharyngeal carcinoma (NPC) patients who developed distant metastasis are characterized by senescence phenotypes, in which circWDR37 is a key regulator. CircW...

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Autores principales: Li, Qian, Zhao, Yu‐Heng, Xu, Cheng, Liang, Ye‐Lin, Zhao, Yin, He, Qing‐Mei, Li, Jun‐Yan, Chen, Kai‐Lin, Qiao, Han, Liu, Na, Ma, Jun, Chen, Lei, Li, Ying‐Qin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015868/
https://www.ncbi.nlm.nih.gov/pubmed/36683218
http://dx.doi.org/10.1002/advs.202205668
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author Li, Qian
Zhao, Yu‐Heng
Xu, Cheng
Liang, Ye‐Lin
Zhao, Yin
He, Qing‐Mei
Li, Jun‐Yan
Chen, Kai‐Lin
Qiao, Han
Liu, Na
Ma, Jun
Chen, Lei
Li, Ying‐Qin
author_facet Li, Qian
Zhao, Yu‐Heng
Xu, Cheng
Liang, Ye‐Lin
Zhao, Yin
He, Qing‐Mei
Li, Jun‐Yan
Chen, Kai‐Lin
Qiao, Han
Liu, Na
Ma, Jun
Chen, Lei
Li, Ying‐Qin
author_sort Li, Qian
collection PubMed
description Senescence is associated with tumor metastasis and chemotherapy resistance, yet the mechanisms remain elusive. Here, it is identified that nasopharyngeal carcinoma (NPC) patients who developed distant metastasis are characterized by senescence phenotypes, in which circWDR37 is a key regulator. CircWDR37 deficiency limits cisplatin or gemcitabine‐induced senescent NPC cells from proliferation, migration, and invasion. Mechanistically, circWDR37 binds to and dimerizes double‐stranded RNA‐activated protein kinase R (PKR) to initiate PKR autophosphorylation and activation. Independent of its kinase activity, phosphorylated PKR induces I‐kappaB kinase beta (IKKβ) phosphorylation, binds to and releases RELA from NF‐κB inhibitor alpha (IκBα) to trigger nuclear factor kappa B (NF‐κB) activation, thereby stimulating cyclin D1 (CCND1) and senescence‐associated secretory phenotype component gene transcription in a circWDR37‐dependent manner. Low circWDR37 levels correlate with chemotherapy response and favorable survival in NPC patients treated with gemcitabine or cisplatin induction chemotherapy. This study uncovers a new mechanism of circWDR37 activated PKR in senescence‐driven metastasis and provides appealing therapeutic targets in NPC.
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spelling pubmed-100158682023-03-16 Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation Li, Qian Zhao, Yu‐Heng Xu, Cheng Liang, Ye‐Lin Zhao, Yin He, Qing‐Mei Li, Jun‐Yan Chen, Kai‐Lin Qiao, Han Liu, Na Ma, Jun Chen, Lei Li, Ying‐Qin Adv Sci (Weinh) Research Articles Senescence is associated with tumor metastasis and chemotherapy resistance, yet the mechanisms remain elusive. Here, it is identified that nasopharyngeal carcinoma (NPC) patients who developed distant metastasis are characterized by senescence phenotypes, in which circWDR37 is a key regulator. CircWDR37 deficiency limits cisplatin or gemcitabine‐induced senescent NPC cells from proliferation, migration, and invasion. Mechanistically, circWDR37 binds to and dimerizes double‐stranded RNA‐activated protein kinase R (PKR) to initiate PKR autophosphorylation and activation. Independent of its kinase activity, phosphorylated PKR induces I‐kappaB kinase beta (IKKβ) phosphorylation, binds to and releases RELA from NF‐κB inhibitor alpha (IκBα) to trigger nuclear factor kappa B (NF‐κB) activation, thereby stimulating cyclin D1 (CCND1) and senescence‐associated secretory phenotype component gene transcription in a circWDR37‐dependent manner. Low circWDR37 levels correlate with chemotherapy response and favorable survival in NPC patients treated with gemcitabine or cisplatin induction chemotherapy. This study uncovers a new mechanism of circWDR37 activated PKR in senescence‐driven metastasis and provides appealing therapeutic targets in NPC. John Wiley and Sons Inc. 2023-01-22 /pmc/articles/PMC10015868/ /pubmed/36683218 http://dx.doi.org/10.1002/advs.202205668 Text en © 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Li, Qian
Zhao, Yu‐Heng
Xu, Cheng
Liang, Ye‐Lin
Zhao, Yin
He, Qing‐Mei
Li, Jun‐Yan
Chen, Kai‐Lin
Qiao, Han
Liu, Na
Ma, Jun
Chen, Lei
Li, Ying‐Qin
Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation
title Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation
title_full Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation
title_fullStr Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation
title_full_unstemmed Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation
title_short Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation
title_sort chemotherapy‐induced senescence reprogramming promotes nasopharyngeal carcinoma metastasis by circrna‐mediated pkr activation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015868/
https://www.ncbi.nlm.nih.gov/pubmed/36683218
http://dx.doi.org/10.1002/advs.202205668
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