Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function
Abstract Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infecti...
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Nature Portfolio
2024-11-01
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| author | Linli Chen Xiaojing Guo Wen Lin Yingying Huang Suling Zhuang Qianfeng Li Jianhua Xu Shengnan Ye |
| author_facet | Linli Chen Xiaojing Guo Wen Lin Yingying Huang Suling Zhuang Qianfeng Li Jianhua Xu Shengnan Ye |
| author_sort | Linli Chen |
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| description | Abstract Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies. |
| format | Article |
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| institution | DOAJ |
| issn | 2045-2322 |
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| publishDate | 2024-11-01 |
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| spelling | doaj-art-e93f8d5ceb9a48afa801854df8aea4b62025-08-20T02:49:58ZengNature PortfolioScientific Reports2045-23222024-11-0114111510.1038/s41598-024-77294-wCurcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 functionLinli Chen0Xiaojing Guo1Wen Lin2Yingying Huang3Suling Zhuang4Qianfeng Li5Jianhua Xu6Shengnan Ye7Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical UniversityThe School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical UniversityAbstract Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.https://doi.org/10.1038/s41598-024-77294-wEpstein–Barr virusCurcumin derivativeHsp90 inhibitorLytic induction therapyNasopharyngeal carcinomaGastric carcinoma |
| spellingShingle | Linli Chen Xiaojing Guo Wen Lin Yingying Huang Suling Zhuang Qianfeng Li Jianhua Xu Shengnan Ye Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function Scientific Reports Epstein–Barr virus Curcumin derivative Hsp90 inhibitor Lytic induction therapy Nasopharyngeal carcinoma Gastric carcinoma |
| title | Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function |
| title_full | Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function |
| title_fullStr | Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function |
| title_full_unstemmed | Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function |
| title_short | Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function |
| title_sort | curcumin derivative c210 induces epstein barr virus lytic cycle and inhibits virion production by disrupting hsp90 function |
| topic | Epstein–Barr virus Curcumin derivative Hsp90 inhibitor Lytic induction therapy Nasopharyngeal carcinoma Gastric carcinoma |
| url | https://doi.org/10.1038/s41598-024-77294-w |
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