Epstein-Barr virus latent membrane protein 1 induces the chemotherapeutic target, thymidine phosphorylase, via NF-kappaB and p38 MAPK pathways.
High thymidine phosphorylase (TP) expression is significantly correlated with poor prognosis in patients with nasopharyngeal carcinoma (NPC). NPC is an Epstein-Barr Virus (EBV)-associated cancer in which the EBV-encoded oncogene product, latent membrane protein 1 (LMP1), is expressed in approximately 60% of tumor tissues. However, no previous study has examined whether LMP1 is involved in up-regulating TP expression in NPC tissues. We herein show that LMP1 expression is correlated with TP expression in tumor cells, as examined by quantitative RT-PCR and immunohistochemical staining. We further show that the CTAR1 and CTAR2 domains of LMP1 mediate TP induction, as demonstrated by quantitative RT-PCR and Western blot analyses using LMP1 deletion and site-specific mutants. Mechanistically, LMP1-mediated TP induction is abolished by inhibitors of NF-kappaB and p38 MAPK, dominant-negative IkappaB and p38, and siRNA-mediated knockdown of p38 MAPK. Clinically, there were significant correlations among the expression levels of TP, activated p65, and phospho-p38 MAPK in NPC biopsy samples. Functionally, LMP1-mediated induction of TP expression enhanced the sensitivity of NPC cells to the chemotherapeutic prodrug, 5'-DFUR. Our results provide new insights into the roles of LMP1-mediated NF-kappaB and p38 MAPK signaling pathways in TP induction, potentially suggesting new therapeutic strategies for the treatment of NPC.
Chen
Chia-Chun
CC
Graduate Institute of Biomedical Sciences, Chang Gung University, 259, Wen-Hwa 1st Road, Kwei-Shan, Taoyuan 333, Taiwan. d9401210@stmail.cgu.edu.tw
Chen
Lih-Chyang
LC
Liang
Ying
Y
Tsang
Ngan-Ming
NM
Chang
Yu-Sun
YS
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002277:Carcinoma / Q000201:enzymology* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D005467:Floxuridine / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000821:virology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D005467:Floxuridine; D013939:Thymidine Phosphorylase; D048051:p38 Mitogen-Activated Protein Kinases; C025034:doxifluridine