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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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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. |
format | Online Article Text |
id | pubmed-10015868 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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