Abstract
Nasopharyngeal carcinoma (NPC) is a unique malignancy derived from the epithelium of the nasopharynx. Despite great advances in the development of radiotherapy and chemotherapy, relapse and metastasis in NPC patients remain major causes of mortality. Evidence accumulated over recent years indicates that Epstein-Barr virus (EBV) lytic replication plays an important role in the pathogenesis of NPC and inhibition of EBV reactivation is now being considered as a goal for the therapy of EBV-associated cancers. With this in mind, a panel of dietary compounds was screened and emodin was found to have potential anti-EBV activity. Through Western blotting, immunofluorescence, and flow cytometric analysis, we show that emodin inhibits the expression of EBV lytic proteins and blocks virion production in EBV- positive epithelial cell lines. In investigating the underlying mechanism, reporter assays indicated that emodin represses Zta promoter (Zp) and Rta promoter (Rp) activities, triggered by various inducers. Mapping of the Zp construct reveals that the SP1 binding region is important for emodin-triggered repression and emodin is shown to be able to inhibit SP1 expression, suggesting that it likely inhibits EBV reactivation by suppression of SP1 expression. Moreover, we also show that emodin inhibits the tumorigenic properties induced by repeated EBV reactivation, including micronucleus formation, cell proliferation, migration, and matrigel invasiveness. Emodin administration also represses the tumor growth in mice which is induced by EBV activation. Taken together, our results provide a potential chemopreventive agent in restricting EBV reactivation and NPC recurrence.
Highlights
Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma rising at the post nasal cavity, which is prevalent in southern China, southeastern Asia, and Taiwan
The cells were seeded into 96-well plates 24 h prior to treatment; emodin was added for 48 h to determine its cytotoxic effect on the NPC cell lines NA and HA
With 24 h induction by TPA + sodium butyrate (SB), the percentage of EADAfter we demonstrated that emodin blocks the expression of Epstein-Barr virus (EBV) lytic proteins, a further question positive NA cells was 68%, while this reduced to 30% and 15% after treatment with 10 μM and 20 μM
Summary
Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma rising at the post nasal cavity, which is prevalent in southern China, southeastern Asia, and Taiwan. 80,000 cases of NPC are reported each year, 0.7% of all cancers [1]. The 5-year survival rate of NPC is 60%. When treatment begins at an early stage, the 5-year survival rate can reach 80–95%; it is poor at a later stage of NPC [2]. Radiotherapy is the primary and effective treatment for NPC. The combination of radiotherapy with neoadjuvant chemotherapy is another pivotal treatment for NPC patients and increases the survival rate significantly [3,4,5]. The therapeutic efficiency of NPC management has largely been improved, how to avoid NPC metastasis is still an urgent unmet need
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