EBV‐Encoded LMP‐1 Sensitizes Nasopharyngeal Carcinoma Cells to Genotoxic Drugs by Down‐Regulating Cabin1 Expression

Abstract

The oncogenic latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is involved in the pathogenesis of human nasopharyngeal carcinoma (NPC) and lymphoma. We and other authors have shown earlier that LMP1 induces apoptosis and inhibits xenograft tumor growth in mice, but the mechanism underlying these processes has not been investigated so far. In the present study, we show that knockdown of LMP1 renders the EBV-positive NPC cell line CG-1 resistant to various genotoxic drugs (cisplatin, etoposide, and adriamycin). LMP1 inhibits the expression of Cabin1, a Ca(2+) regulated protein shown earlier to inhibit calcineurin. Knockdown of calcineurin binding protein (Cabin1) with small hairpin RNA sensitizes CG-1 cells to genotoxic drugs. In contrast, LMP1 overexpression reduces Cabin1 level and renders both CG-1 cells and EBV-negative NPC cell lines sensitive to cisplatin. The c-Jun-N-terminal kinase (JNK) and ERK pathways are required for LMP1-induced suppression of Cabin1 at the transcriptional level. Chromatin immunoprecipitation assays further confirm that the JNK-activated transcription factor AP-1 mediates the LMP1-induced down-regulation of Cabin1 gene expression. LMP1 knockdown also increases the resistance of xenograph tumors to cisplatin in mice, therefore confirming the relevance of our findings in vivo. This study reveals the molecular mechanism underlying the pro-apoptotic activity of LMP1 during cisplatin-based NPC chemotherapy.

JNK pathway inhibition enhances chemotherapeutic sensitivity to Adriamycin in nasopharyngeal carcinoma cells

“…Treatment with chemotherapeutic drugs activates several biochemical signaling pathways, including the c-Jun N-terminal kinase (JNK) pathway (5). JNKs are serine/threonine kinases that belong to the mitogen-activated protein kinase family (6), and are responsive to diverse stress (7,8).…”

Epstein-Barr Virus_Encoded LMP1 Upregulates MicroRNA-21 to Promote the Resistance of Nasopharyngeal Carcinoma Cells to Cisplatin-Induced Apoptosis by Suppressing PDCD4 and Fas-L

“…Previous studies have found that LMP1 have double effects: the cytotoxic and oncogenic effects [57,58]. Although Pu-Yuan Chang et al [59] found that LMP1 can sensitize nasopharyngeal carcinoma cells to genotoxic drugs (cisplatin, etoposide, and adriamycin), but the cell line CG-1 in above study was difference from the cell lines used in our study including the region, histopathology and the way of EBV infection. Guillaume Brocqueville et al [60] found that the cytotoxic and oncogenic effects of LMP1 are not mutually exclusive but may operate sequentially.…”

iTRAQ-based quantitative proteomic analysis of differentially expressed proteins in chemoresistant nasopharyngeal carcinoma

“…Currently, many studies have identified proteins or genes in chemotherapy-resistant NPC, [32][33][34][35] but only the differences between the drug-resistant cell and its parent cell are discussed. 32 In this study, we established two drug-resistant cell lines at the same time to screen for differences common to both cell lines.…”