Epstein-Barr virus latent membrane protein 1 induces the chemotherapeutic target, thymidine phosphorylase, via NF-kappaB and p38 MAPK pathways

Cell Signal. 2010 Jul;22(7):1132-42. doi: 10.1016/j.cellsig.2010.03.008. Epub 2010 Mar 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Carcinoma / enzymology*
  • Carcinoma / metabolism
  • Carcinoma / virology
  • Cell Line, Tumor
  • Floxuridine / pharmacology
  • Humans
  • NF-kappa B / metabolism*
  • Nasopharyngeal Neoplasms / enzymology*
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / virology
  • Protein Structure, Tertiary
  • Signal Transduction
  • Thymidine Phosphorylase / antagonists & inhibitors
  • Thymidine Phosphorylase / metabolism*
  • Viral Matrix Proteins / analysis
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Antimetabolites, Antineoplastic
  • EBV-associated membrane antigen, Epstein-Barr virus
  • NF-kappa B
  • Viral Matrix Proteins
  • Floxuridine
  • Thymidine Phosphorylase
  • p38 Mitogen-Activated Protein Kinases
  • doxifluridine