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Epstein-Barr 病毒潜伏膜蛋白 1 通过激活 MEK1/2/Nrf-2 信号通路增强 T 细胞淋巴瘤自噬和顺铂耐药性。

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.

机构信息

Department of Pathology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Sciences, Xiangyang, 441021 Hubei, China.

Department of Pathology Teaching and Research Section, Xiangyang Polytechnic, Xiangyang, 441050 Hubei, China.

出版信息

Anal Cell Pathol (Amst). 2021 Jun 18;2021:6668947. doi: 10.1155/2021/6668947. eCollection 2021.

DOI:10.1155/2021/6668947
PMID:34239803
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8235988/
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.

摘要

EBV-LMP1（Epstein-Barr 病毒潜伏膜蛋白 1）与淋巴瘤有关，但具体机制仍存在争议。本研究旨在通过 MEK1/2/Nrf-2 信号通路研究 EBV-LMP1 对淋巴瘤耐药性的调节。首先，在 EBV 阳性的 SNK-6 细胞中敲低 LMP1，并在 EBV 阴性的 KHYG-1 细胞中过表达 LMP1。结果发现，过表达 LMP1 显著促进了 KHYG-1 细胞对顺铂（DDP）的耐药性，这与细胞中自噬的增加有关。相反，在 SNK-6 细胞中敲低 LMP1 表达则促进了细胞对 DDP 的敏感性，并减少了 DDP 处理后细胞的自噬。此外，在 KHYG-1 细胞中特异性抑制自噬显著减弱了 LMP1 过表达引起的对 DDP 的耐药性，但在 SNK-6 细胞中用雷帕霉素处理则显著促进了细胞的自噬。随后，过表达 LMP1 促进了 KYHG-1 细胞中 MEK1/2-Nrf2 通路的激活，而在 SNK-6 细胞中敲低 LMP1 则抑制了 MEK1/2-Nrf2 通路的激活。抑制 MEK1/2/Nrf-2 阻断了 LMP1 对淋巴瘤细胞耐药性的促进作用。综上所述，EBV-LMP1 通过激活淋巴瘤细胞中的 MEK1/2/Nrf-2 信号通路，促进 DDP 处理后细胞自噬，从而增强淋巴瘤细胞对 DDP 的耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eed6/8235988/f61d62572822/ACP2021-6668947.005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eed6/8235988/ac30814f6506/ACP2021-6668947.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eed6/8235988/920c9e3f9e5c/ACP2021-6668947.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eed6/8235988/4a97120f6c0e/ACP2021-6668947.003.jpg
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