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LMP1 Increases Expression of NADPH Oxidase (NOX) and Its Regulatory Subunit p22 in NP69 Nasopharyngeal Cells and Makes Them Sensitive to a Treatment by a NOX Inhibitor.

Sun J, Hu C, Zhu Y, Sun R, Fang Y, Fan Y, Xu F - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R.China.

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.

No MeSH data available.


Related in: MedlinePlus

A positive correlation between LMP1 and p22phox expression was detected in nasopharyngeal carcinoma.A: The distributions of NPC tissue samples and non-NPC tissue samples with LMP1high/ p22phox high, LMP1low/p22phox low, LMP1high/p22phox low and LMP1low/p22phox high were determined with SPSS correlation analysis. B: In a tissue array, the p22phox and LMP1 expression levels were detected in NPC cancer tissues using an IHC assay. P1 and P2 represents two NPC tissues from patients with distinctive p22phox and LMP1 expression pattern. P1 tissue has low p22phox and LMP1 expression level, and P2 has higher LMP1 and p22phox expression level. NPC tissue sample with LMP1 negative and p22phox were served as negative control (magnification × 400).
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pone.0134896.g004: A positive correlation between LMP1 and p22phox expression was detected in nasopharyngeal carcinoma.A: The distributions of NPC tissue samples and non-NPC tissue samples with LMP1high/ p22phox high, LMP1low/p22phox low, LMP1high/p22phox low and LMP1low/p22phox high were determined with SPSS correlation analysis. B: In a tissue array, the p22phox and LMP1 expression levels were detected in NPC cancer tissues using an IHC assay. P1 and P2 represents two NPC tissues from patients with distinctive p22phox and LMP1 expression pattern. P1 tissue has low p22phox and LMP1 expression level, and P2 has higher LMP1 and p22phox expression level. NPC tissue sample with LMP1 negative and p22phox were served as negative control (magnification × 400).

Mentions: Given the role of p22phox in LMP1-mediated NOX activation and the metabolic disorder characterizing NPC cells, we investigated whether p22phox overexpression is associated with LMP1 expression in NPC patients. We examined p22phox and LMP1 expression levels in 30 NPC and 19 non-cancerous tissue samples. In NPC tissue samples, p22phox expression was significantly correlated with LMP1expression (n = 30, p = 0.007, Table 1), whereas no significant correlation between p22phox and LMP1 mRNA levels was detected in nasopharyngeal non-cancerous tissues (n = 19, p = 0.679). Approximately 40% of NPC samples were LMP1high/ p22phox high, and 33.33% of the NPC samples were LMP1low/p22phox low. In contrast, the percentages of samples with LMP1high/p22phox low and LMP1low/p22phox high correlations were lower (10% and 16.67%, respectively). However, out of the 19 non-cancerous tissues, LMP1 expression was only detected in 14 samples, whereas p22phox was equally detected in both the LMP1negative and the LMP1high samples (Fig 4A). Of the 30 patients whose tumor biopsies were used in the NPC tissue assay (Fig 4B), p22phox levels were also correlated with LMP1 expression in NPC tissues. P1 and P2 represents the NPC tissues from patients P1 and P2 with distinctive p22phox and LMP1 expression pattern. P1 tissue has low p22phox and LMP1 expression level, and P2 has higher LMP1 and p22phox expression level. NPC tissue sample with LMP1 negative and p22phox were served as negative control. These data confirmed the correlation between p22phox and LMP1 expression in NPC tissue samples.


LMP1 Increases Expression of NADPH Oxidase (NOX) and Its Regulatory Subunit p22 in NP69 Nasopharyngeal Cells and Makes Them Sensitive to a Treatment by a NOX Inhibitor.

Sun J, Hu C, Zhu Y, Sun R, Fang Y, Fan Y, Xu F - PLoS ONE (2015)

A positive correlation between LMP1 and p22phox expression was detected in nasopharyngeal carcinoma.A: The distributions of NPC tissue samples and non-NPC tissue samples with LMP1high/ p22phox high, LMP1low/p22phox low, LMP1high/p22phox low and LMP1low/p22phox high were determined with SPSS correlation analysis. B: In a tissue array, the p22phox and LMP1 expression levels were detected in NPC cancer tissues using an IHC assay. P1 and P2 represents two NPC tissues from patients with distinctive p22phox and LMP1 expression pattern. P1 tissue has low p22phox and LMP1 expression level, and P2 has higher LMP1 and p22phox expression level. NPC tissue sample with LMP1 negative and p22phox were served as negative control (magnification × 400).
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pone.0134896.g004: A positive correlation between LMP1 and p22phox expression was detected in nasopharyngeal carcinoma.A: The distributions of NPC tissue samples and non-NPC tissue samples with LMP1high/ p22phox high, LMP1low/p22phox low, LMP1high/p22phox low and LMP1low/p22phox high were determined with SPSS correlation analysis. B: In a tissue array, the p22phox and LMP1 expression levels were detected in NPC cancer tissues using an IHC assay. P1 and P2 represents two NPC tissues from patients with distinctive p22phox and LMP1 expression pattern. P1 tissue has low p22phox and LMP1 expression level, and P2 has higher LMP1 and p22phox expression level. NPC tissue sample with LMP1 negative and p22phox were served as negative control (magnification × 400).
Mentions: Given the role of p22phox in LMP1-mediated NOX activation and the metabolic disorder characterizing NPC cells, we investigated whether p22phox overexpression is associated with LMP1 expression in NPC patients. We examined p22phox and LMP1 expression levels in 30 NPC and 19 non-cancerous tissue samples. In NPC tissue samples, p22phox expression was significantly correlated with LMP1expression (n = 30, p = 0.007, Table 1), whereas no significant correlation between p22phox and LMP1 mRNA levels was detected in nasopharyngeal non-cancerous tissues (n = 19, p = 0.679). Approximately 40% of NPC samples were LMP1high/ p22phox high, and 33.33% of the NPC samples were LMP1low/p22phox low. In contrast, the percentages of samples with LMP1high/p22phox low and LMP1low/p22phox high correlations were lower (10% and 16.67%, respectively). However, out of the 19 non-cancerous tissues, LMP1 expression was only detected in 14 samples, whereas p22phox was equally detected in both the LMP1negative and the LMP1high samples (Fig 4A). Of the 30 patients whose tumor biopsies were used in the NPC tissue assay (Fig 4B), p22phox levels were also correlated with LMP1 expression in NPC tissues. P1 and P2 represents the NPC tissues from patients P1 and P2 with distinctive p22phox and LMP1 expression pattern. P1 tissue has low p22phox and LMP1 expression level, and P2 has higher LMP1 and p22phox expression level. NPC tissue sample with LMP1 negative and p22phox were served as negative control. These data confirmed the correlation between p22phox and LMP1 expression in NPC tissue samples.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P.R.China.

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.

No MeSH data available.


Related in: MedlinePlus