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J Exp Clin Cancer Res. 2018 Aug 15;37(1):192. doi: 10.1186/s13046-018-0865-5.

Triptolide inhibits Epstein-Barr nuclear antigen 1 expression by increasing sensitivity of mitochondria apoptosis of nasopharyngeal carcinoma cells.

Author information

1
The State Key Laboratory of Virology, Department of Pathogen Biology, School of Basic Medical Sciences, Hubei Province Key Laboratory of Allergy and Immune-related Diseases, Wuhan University, 185 Eastlake Road, Wuhan, 430071, People's Republic of China.
2
Department of Pathology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430060, People's Republic of China.
3
Department of Pathogen Biology, Weifang Medical University, Weifang, 261053, People's Republic of China.
4
Department of corneal disease, Weifang Eye Hospital, Weifang, 261041, People's Republic of China.
5
The State Key Laboratory of Virology, Department of Pathogen Biology, School of Basic Medical Sciences, Hubei Province Key Laboratory of Allergy and Immune-related Diseases, Wuhan University, 185 Eastlake Road, Wuhan, 430071, People's Republic of China. xsun6@whu.edu.cn.

Abstract

BACKGROUND:

Epstein-Barr virus (EBV) is widely found in nasopharyngeal carcinoma (NPC) tissue and associated with poor prognosis of patients. EBV nuclear antigen 1 (EBNA1) is expressed in all NPC tumors and plays multiple biological roles in both virus and host cells. Triptolide is a natural product extracted from Tripterygium and shows anti-cancer activities. The goal of this work was to illustrate the anti-cancer effect of triptolide and elucidate a novel anti-apoptotic mechanism of EBNA1 in NPC cells encountered with triptolide.

METHODS:

In the present study, a CCK-8 assay was used to analyze the proliferation of NPC cells treated with triptolide in a dose- and time-dependent ways. Effects of triptolide on NPC cell cycle and apoptosis were investigated by flow cytometric analysis. EBNA1 expression in mRNA and protein levels was determined by quantitative real-time PCR and Western blot, respectively.

RESULTS:

Our results showed that triptolide effectively inhibited proliferation of NPC cells. Triptolide arrested NPC cell cycles in S phase and induced apoptosis through a caspase-9-dependent apoptosis pathway. Low-dose of triptolide reduced the half-life of EBNA1 and significantly decreased EBNA1 expression by promoting the process of proteasome-ubiquitin pathway. Over-expression of EBNA1, which was independent from EBV genome, effectively attenuated the apoptosis induced by triptolide. In addition, triptolide significantly inhibited proliferations of tumors induced by EBV-positive cells in vivo. Furthermore, EBNA1 were expressed in all NPC biopsies of Chinese patients.

CONCLUSIONS:

In summary, our study provides the evidence that triptolide induces EBNA1 degradation and stimulates NPC apoptosis through mitochondria apoptotic pathway. In addition, EBNA1 assists NPC cells to resist triptolide-induced apoptosis through inhibiting caspase-9-dependent apoptotic pathway.

KEYWORDS:

Apoptosis; Caspase-9; EBNA1; NPC; Triptolide

PMID:
30111354
PMCID:
PMC6094928
DOI:
10.1186/s13046-018-0865-5
[Indexed for MEDLINE]
Free PMC Article

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