Open Access

ARTICLE

(−)-Epigallocatechin-3-Gallate Inhibits EBV Lytic Replication via Targeting LMP1-Mediated MAPK Signal Axes

Hongde Li^*†‡, Yueshuo Li^*†‡, Jianmin Hu^*†‡, Sufang Liu^§, Xiangjian Luo^*†‡¶, Min Tang^*†‡, Ann M. Bode^#, Zigang Dong^#**, Xinqi Liu^††, Weihua Liao^‡‡, Ya Cao^{*†‡¶ §§¶¶}

* Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, P.R. China
† Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha, P.R. China
‡ Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, P.R. China
§ Division of Hematology, Institute of Molecular Hematology, the Second Xiangya Hospital, Central South University at Changsha, Changsha, P.R. China
¶ Molecular Imaging Research Center of Central South University, Changsha, P.R. China
# The Hormel Institute, University of Minnesota, Austin, MN, USA
** College of Medicine, Zhengzhou University, Zhengzhou, P.R. China
†† State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University at Tianjin, Tianjin, P.R. China
‡‡ Department of Radiology, Xiangya Hospital, Central South University at Changsha, Changsha, P.R. China
§§ Research Center for Technologies of Nucleic Acid Based Diagnostics and Therapeutics Hunan Province, Changsha, P.R. China
¶¶ National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, Changsha, P.R. China

Oncology Research 2020, 28(7-8), 763-778. https://doi.org/10.3727/096504021X16135618512563

Abstract

Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) plays an important oncogenic role in the viral latent infection. Recently, increasing evidence indicates that the high expression of LMP1 during EBV lytic cycle is related to the viral lytic replication. However, the mechanism by which LMP1 regulates EBV lytic replication remains unclear. (−)-Epigallocatechin-3-gallate (EGCG) prevents carcinogenesis by directly targeting numerous membrane proteins and effectively inhibits EBV lytic cascade. Here, we demonstrated that LMP1 promotes EBV lytic replication through the downstream signal molecules MAPKs, including ERKs, p38, and JNKs. LMP1 induces the phosphorylation of p53 through MAPKs to enhance the ability of wild-type p53 (wt-p53) to activate expression of BZLF1 gene, while the JNKs/c-Jun signal axis appears to be involved in EBV lytic replication induced by LMP1 in p53 mutant manner. We provided the first evidence that EGCG directly targets the viral membrane LMP1 (K_d = 0.36 μM, n = 1) using fluorescence quenching, isothermal titration calorimetry (ITC) assay, and CNBR-activated Sepharose 4B pull-down affinity chromatography. Furthermore, we revealed that EGCG inhibits EBV lytic replication via suppressing LMP1 and thus blocking the downstream MAPKs/wt-p53 signal axis in AGS-EBV cells and JNKs/c-Jun signal axis in p53 mutant B95.8 cells. Our study, for the first time, reports the binding and inhibitory efficacy of EGCG to the LMP1, which is a key oncoprotein encoded by EBV. These findings suggest the novel function of LMP1 in the regulation of EBV lytic cycle and reveal the new role of EGCG in EBV-associated malignancies through suppressing viral reactivation.

---

Keywords

---