Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy.
Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy.
复制标题
作者：
我们这项工作的目标是阐明 Epstein-Barr 病毒 (EBV) 调节的整体生化特征，并提供一个新的代谢相关靶点来改善鼻咽癌 (NPC) 的治疗方案。我们使用代谢组学方法研究 EBV 调节的代谢变化，发现 EBV 编码的潜伏膜蛋白 1 (LMP1) 的外源过度表达显着增加糖酵解。包括己糖激酶 2 (HK2) 在内的多种糖酵解基因的失调被确定与 LMP1 介导的 NPC 细胞中葡萄糖代谢的重编程有关。 HK2 的上调可提高有氧糖酵解并通过阻止细胞凋亡促进增殖。更重要的是，HK2在鼻咽癌活检中与LMP1呈正相关，高HK2水平与鼻咽癌患者放疗后较差的总生存率显着相关。 HK2的敲低有效增强了LMP1过表达的NPC细胞对辐射的敏感性。最后，c-Myc 被证明是 LMP1 诱导的 HK2 上调所必需的。 LMP1 介导的 PI3-K/Akt-GSK3beta-FBW7 信号轴减弱导致 c-Myc 稳定。这些发现表明 EBV 与 NPC 糖酵解之间存在密切关系。值得注意的是，LMP1 是 NPC 细胞中 EBV 介导的糖酵解重编程的关键调节因子。鉴于 EBV 介导的糖酵解失调的重要性，抗糖酵解疗法可能是治疗 EBV 相关癌症的一个值得探索的途径。
Our goal in this work was to illustrate the Epstein-Barr virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV-encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The upregulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced upregulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers.
登录
查看更多内容
影响因子：
3.7
作者：
Ma X;Yang L;Xiao L;Tang M;Liu L;Li Z;Deng M;Sun L;Cao Y
通讯作者：
Cao Y
影响因子：
11.2
作者：
Kondo, Satoru;Seo, So Young;Pagano, Joseph S.
通讯作者：
Pagano, Joseph S.
影响因子：
5.7
作者：
Noch E;Khalili K
通讯作者：
Khalili K
EBV潜在膜蛋白1在B细胞淋巴瘤中激活AKT，NFKAPPAB和STAT3。
影响因子：
6.7
作者：
Shair, Kathy H Y;Bendt, Katherine M;Edwards, Rachel H;Bedford, Elisabeth C;Nielsen, Judith N;Raab-Traub, Nancy
通讯作者：
Raab-Traub, Nancy
DOI：
10.1073/pnas.1004882107
发表时间：
2010-06-08
影响因子：
11.1
作者：
Delgado, Tracie;Carroll, Patrick A.;Lagunoff, Michael
通讯作者：
Lagunoff, Michael