Abstract
Oxidative stress is thought to contribute to cancer development. Epstein-Barr virus (EBV) and its encoded oncoprotein, latent membrane protein 1 (LMP1), are closely associated with the transformation of nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma (BL). In this study, we used LMP1-transformed NP cells and EBV-related malignant cell lines to assess the effects of LMP1 on reactive oxygen species (ROS) accumulation and glycolytic activity. Using NPC tissue samples and a tissue array to address clinical implications, we report that LMP1 activates NAD(P)H oxidases to generate excessive amount of ROS in EBV-related malignant diseases. By evaluating NAD(P)H oxidase (NOX) subunit expression, we found that the expression of the NAD(P)H oxidase regulatory subunit p22phox was significantly upregulated upon LMP1-induced transformation. Furthermore, this upregulation was mediated by the c-Jun N-terminal kinase (JNK) pathway. In addition, LMP1 markedly stimulated anaerobic glycolytic activity through the PI3K/Akt pathway. Additionally, in both NPC cells and tissue samples, p22phox expression correlated with LMP1 expression. The NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI) also exerted a marked cytotoxic effect in LMP1-transformed and malignant cells, providing a novel strategy for anticancer therapy.
MeSH terms
-
Carcinoma
-
Cell Line
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
Cell Survival / genetics
-
Cell Transformation, Neoplastic / genetics*
-
Cell Transformation, Neoplastic / metabolism
-
Enzyme Inhibitors / pharmacology
-
Epithelial Cells / metabolism
-
Epithelial Cells / pathology
-
Epithelial Cells / virology
-
Gene Expression Regulation, Neoplastic
-
Glycolysis
-
Herpesvirus 4, Human / genetics*
-
Herpesvirus 4, Human / metabolism
-
Herpesvirus 4, Human / physiology
-
Host-Pathogen Interactions / genetics
-
Humans
-
Immunoblotting
-
Immunohistochemistry
-
JNK Mitogen-Activated Protein Kinases / metabolism
-
NADPH Oxidases / antagonists & inhibitors
-
NADPH Oxidases / genetics*
-
NADPH Oxidases / metabolism
-
Nasopharyngeal Carcinoma
-
Nasopharyngeal Neoplasms / genetics
-
Nasopharyngeal Neoplasms / metabolism
-
Nasopharyngeal Neoplasms / virology
-
Nasopharynx / metabolism
-
Nasopharynx / pathology
-
Nasopharynx / virology
-
Onium Compounds / pharmacology
-
Phosphatidylinositol 3-Kinases / metabolism
-
Proto-Oncogene Proteins c-akt / metabolism
-
Reactive Oxygen Species / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Viral Matrix Proteins / genetics*
-
Viral Matrix Proteins / metabolism
Substances
-
EBV-associated membrane antigen, Epstein-Barr virus
-
Enzyme Inhibitors
-
Onium Compounds
-
Reactive Oxygen Species
-
Viral Matrix Proteins
-
diphenyleneiodonium
-
NADPH Oxidases
-
CYBA protein, human
-
Phosphatidylinositol 3-Kinases
-
Proto-Oncogene Proteins c-akt
-
JNK Mitogen-Activated Protein Kinases
Grants and funding
The authors received no specific funding for this work.