A new study reveals how C210, a curcumin derivative, selectively reactivates Epstein–Barr virus to kill cancer cells without infectious risks, paving the way for safer, targeted cancer therapies.
Study: Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function. Image Credit: Stephanie Frey / Shutterstock
A study published in the journal Scientific Reports identifies a novel curcumin derivative that can effectively induce the Epstein–Barr virus (EBV) lytic cycle by disrupting heat shock protein 90 (HSP90).
Background
Epstein–Barr virus (EBV) is a tumorigenic virus associated with a range of cancer types, including epithelial cancers and lymphomas. The virus persists in cancer cells in a latent state, and viral reactivation from the latent state to the lytic state leads to cancer cell death.
Lytic induction therapy has been developed to selectively kill EBV-positive cancer cells by triggering viral reactivation using histone deacetylase inhibitors, DNA methyltransferase inhibitors, proteasome inhibitors, and other chemical compounds. However, the major drawbacks of this therapy are relatively low viral reactivation efficacy and the possibility of producing infectious virions that can subsequently trigger viral diseases or promote oncogenesis.
Curcumin, a plant-derived polyphenol, is capable of inducing the unfolded protein response (UPR) and triggering the EBV lytic cycle in cancer cells. The UPR is a cellular stress response activated upon the accumulation of unfolded proteins in the endoplasmic reticulum (ER).
Heat shock protein 90 (HSP90) is a molecular chaperone that promotes the proper folding and stability of several oncogenic proteins. Small-molecule inhibitors of HSP90 trigger proteasomal or autophagic degradation of HSP90 client proteins and exert antitumor effects.
In this study, scientists have investigated the effect and mode of action of a curcumin derivative, C210 (an HSP90 inhibitor), on EBV lytic induction and infectious virion production in EBV-positive nasopharyngeal carcinoma and gastric carcinoma cell lines.
They have used a conventional lytic inducer, suberoylanilide hydroxamic acid (SAHA; a histone deacetylase inhibitor), to investigate the mode of action of C210.
Important Observations
The study found that the curcumin derivative C210 significantly upregulates RNAs and proteins associated with the EBV lytic cycle in cancer cells without inducing the production of infectious virions. To investigate C210's mode of action, scientists performed HSP90 knockdown experiments and found an induction in lytic RNAs and proteins alongside a reduction in C210-mediated EBV lytic activation, indicating that C210 reactivates EBV from its latent state by inhibiting HSP90.
The scientists also observed that C210 disrupts the binding of HSP90 to its client proteins, signal transducer and activator of transcription 3 (STAT3), and xeroderma pigmentosum group B-complementing protein (XPB), resulting in the proteasomal degradation of these proteins. The C210-induced degradation and depletion of STAT3 levels caused a 2-fold induction in lytic RNA. Scientists suggest that other HSP90 client proteins may also be involved in EBV lytic induction, broadening the scope for potential therapeutic targets.
They further observed that C210-induced STAT3 degradation enhanced the cytotoxic activity and EBV-reactivating capacity of SAHA, a combination effect that resembled STAT3 knockdown results. Regarding the other HSP90 client protein, scientists found that C210-induced degradation of XPB inhibits the expression of SM-dependent late viral genes, thereby suppressing infectious virion production.
SM is an early-phase regulatory viral protein that increases the expression of several late genes required for viral infectivity. Existing evidence suggests that SM interacts with XPB, recruiting it to SM target promoters to specifically induce genes related to virion assembly and infectivity.
Besides inhibiting HSP90 and inducing the EBV lytic cycle, C210 also activates X box binding protein 1 splicing (XBP1s), which then induces the EBV lytic cycle. XBP1s is an active transcription factor that binds to and transactivates the ZII region of the EBV BZLF1 promoter to initiate the latent-to-lytic switch.
Conventional lytic inducers, such as histone deacetylase inhibitors, are known to induce the EBV lytic cycle by promoting histone acetylation. The study findings, however, show that C210 activates the EBV lytic cycle by inhibiting HSP90 function and upregulating XBP1s, two mechanisms that differ from those of established histone deacetylase inhibitors like SAHA.
Study Significance
The study identifies a new curcumin derivative, C210, that acts as an HSP90 inhibitor targeting the EBV lytic cycle. The findings could support the development of novel lytic induction therapies to treat EBV-positive malignancies.
So far, three lytic-inducing drugs, gemcitabine, valproic acid, and ganciclovir, have shown promising outcomes in clinical trials. This emphasizes the need to continue developing and testing new clinical lytic inducers.
Moreover, the study shows that C210 enhances the EBV-reactivating and antitumor effects of SAHA while eliminating SAHA’s negative side effect, infectious virion production. These findings suggest that combination therapy of C210 and SAHA may represent a new approach for EBV-positive cancer treatments. Given the results, the scientists recommend that future preclinical trials investigate C210’s safety and efficacy using animal models of EBV-infected tumors.
Journal reference:
- Chen, L., Guo, X., Lin, W., Huang, Y., Zhuang, S., Li, Q., Xu, J., & Ye, S. (2024). Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function. Scientific Reports, 14(1), 1-15. DOI: 10.1038/s41598-024-77294-w, https://www.nature.com/articles/s41598-024-77294-w