Activation of MEK1/2/Nrf-2 Signaling Pathway by Epstein-Barr Virus-Latent Membrane Protein 1 Enhances Autophagy and Cisplatin Resistance in T-Cell Lymphoma.

Xintao Jia,Mei Zeng,Yuhua Chen,Qiuyu He,Yan Liu,Francisco Aguayo

doi:10.1155/2021/6668947

Abstract

Epstein-Barr virus-latent membrane protein 1 (EBV-LMP1) was associated with lymphoma, but its specific mechanism is still controversial. The study is aimed at studying the regulation of lymphoma resistance by EBV-LMP1 through the MEK1/2/Nrf-2 signaling pathway. First, LMP1 was knocked down in EBV-positive SNK-6 cells and overexpressed in EBV-negative KHYG-1 cells. First, we found that overexpression of LMP1 significantly promoted the resistance of KHYG-1 cells to cisplatin (DDP), which was related to increased autophagy in the cells. In contrast, knockdown of LMP1 expression in SNK-6 cells promoted cellular sensitivity to DDP and reduced the autophagy of cells after DDP treatment. Moreover, specific inhibition of autophagy in KHYG-1 cells significantly attenuated the resistance to DDP caused by overexpression of LMP1, but treatment with rapamycin in SNK-6 cells significantly promoted the autophagy in the cells. Subsequently, overexpression of LMP1 promoted the activation of the MEK1/2-Nrf2 pathway in KYHG-1 cells, whereas knockdown of LMP1 in SNK-6 cells inhibited the activation of the MEK1/2-Nrf2 pathway. Inhibition of MEK1/2/Nrf-2 blocked the promoting effects of LMP1 on lymphoma cell resistance. In conclusion, EBV-LMP1 promotes cell autophagy after DDP treatment by activating the MEK1/2/Nrf-2 signaling pathway in lymphoma cells, thus, enhancing the resistance of lymphoma cells to DDP.

Highlights

Since the discovery of the Epstein-Barr virus (EBV) in African Burkitt lymphoma in 1964, it has been associated with a diverse range of cancer types, including B-cell lymphomas, T-cell/natural killer cell lymphomas, and epithelial malignancies [1]
Colony formation assay found that depletion of Latent membrane protein 1 (LMP1) expression could inhibit the proliferation of SNK-6 cells relative to Scramble, while overexpression of LMP1 could promote the proliferation of KYHG-1 cells versus negative control (NC) (Figure 1(d))
We found that LMP1 silencing increased the cytotoxicity of SNK-6 cells in response to DDP relative to Scramble, but

Summary

Introduction

Since the discovery of the Epstein-Barr virus (EBV) in African Burkitt lymphoma in 1964, it has been associated with a diverse range of cancer types, including B-cell lymphomas, T-cell/natural killer cell lymphomas, and epithelial malignancies [1]. Cisplatin (DDP) is a conventional cytotoxic medicine applied for the treatment of various tumors, including NNKTL, but DDP administration is restricted by its side effects and progress of resistance [5, 6]. It is still unclear whether the EBV-related mechanism is responsible for the resistance of lymphoma cells to DDP-based chemotherapy. We sought to link the DDP resistance with autophagy in lymphoma in the present study and to explore the underlying mechanism

Objectives

Methods

Results

Discussion

Conclusion