Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation
Abstract 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 regulat...
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202205668 |
| _version_ | 1797870207618777088 |
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| author | Qian Li Yu‐Heng Zhao Cheng Xu Ye‐Lin Liang Yin Zhao Qing‐Mei He Jun‐Yan Li Kai‐Lin Chen Han Qiao Na Liu Jun Ma Lei Chen Ying‐Qin Li |
| author_facet | Qian Li Yu‐Heng Zhao Cheng Xu Ye‐Lin Liang Yin Zhao Qing‐Mei He Jun‐Yan Li Kai‐Lin Chen Han Qiao Na Liu Jun Ma Lei Chen Ying‐Qin Li |
| author_sort | Qian Li |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-10T00:24:46Z |
| format | Article |
| id | doaj.art-e2afdafc1b844f9da98b68f00aa26fcb |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-10T00:24:46Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-e2afdafc1b844f9da98b68f00aa26fcb2023-03-15T13:19:15ZengWileyAdvanced Science2198-38442023-03-01108n/an/a10.1002/advs.202205668Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR ActivationQian Li0Yu‐Heng Zhao1Cheng Xu2Ye‐Lin Liang3Yin Zhao4Qing‐Mei He5Jun‐Yan Li6Kai‐Lin Chen7Han Qiao8Na Liu9Jun Ma10Lei Chen11Ying‐Qin Li12Sun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaSun Yat‐sen University Cancer Center the State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Center for Precision Medicine of Sun Yat‐sen University Guangzhou 510060 P. R. ChinaAbstract 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.https://doi.org/10.1002/advs.202205668circWDR37metastasisNF‐κBprotein kinase Rsenescence |
| spellingShingle | Qian Li Yu‐Heng Zhao Cheng Xu Ye‐Lin Liang Yin Zhao Qing‐Mei He Jun‐Yan Li Kai‐Lin Chen Han Qiao Na Liu Jun Ma Lei Chen Ying‐Qin Li Chemotherapy‐Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA‐Mediated PKR Activation Advanced Science circWDR37 metastasis NF‐κB protein kinase R senescence |
| 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 | circWDR37 metastasis NF‐κB protein kinase R senescence |
| url | https://doi.org/10.1002/advs.202205668 |
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