EBV reactivation as a target of luteolin to repress NPC tumorigenesis

// Chung-Chun Wu 1 , Chih-Yeu Fang 1, 4 , Hui-Yu Hsu 1 , Hsin-Ying Chuang 1 , Yu-Jhen Cheng 1 , Yen-Ju Chen 1 , Sheng-Ping Chou 1 , Sheng-Yen Huang 1 , Su-Fang Lin 1 , Yao Chang 2 , Ching-Hwa Tsai 3 , Jen-Yang Chen 1, 3 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan 2 National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan 3 Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan 4 Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan Correspondence to: Jen-Yang Chen, e-mail: cjy@nhri.org.tw Keywords: nasopharyngeal carcinoma, relapse, Epstein-Barr virus, reactivation, luteolin Received: September 12, 2015     Accepted: February 08, 2016     Published: March 08, 2016 ABSTRACT Nasopharyngeal carcinoma (NPC) is a malignancy derived from the epithelial cells of the nasopharynx. Although a combination of radiotherapy with chemotherapy is effective for therapy, relapse and metastasis after remission remain major causes of mortality. Epstein-Barr virus (EBV) is believed to be one of causes of NPC development. We demonstrated previously that EBV reactivation is important for the carcinogenesis of NPC. We sought, therefore, to determine whether EBV reactivation can be a target for retardation of relapse of NPC. After screening, we found luteolin is able to inhibit EBV reactivation. It inhibited EBV lytic protein expression and repressed the promoter activities of two major immediate-early genes, Zta and Rta. Furthermore, luteolin was shown to reduce genomic instability induced by recurrent EBV reactivation in NPC cells. EBV reactivation-induced NPC cell proliferation and migration, as well as matrigel invasiveness, were also repressed by luteolin treatment. Tumorigenicity in mice, induced by EBV reactivation, was decreased profoundly following luteolin administration. Together, these results suggest that inhibition of EBV reactivation is a novel approach to prevent the relapse of NPC.