Curcumin derivative C210 induces Epstein-Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function.

Sci Rep

Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China.

Published: November 2024

AI Article Synopsis

  • *The compound C210, a curcumin derivative, successfully increased EBV lytic activity in cancer cell lines without resulting in infectious virions, indicating a potential treatment pathway.
  • *Research revealed that C210 works by inhibiting Hsp90, leading to the degradation of proteins that promote EBV lytic phase, suggesting it could enhance the effectiveness of other anticancer therapies like SAHA.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535535PMC
http://dx.doi.org/10.1038/s41598-024-77294-wDOI Listing

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