Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
State Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Cell Death Dis. 2024 Aug 20;15(8):604. doi: 10.1038/s41419-024-06999-7.
Natural killer/T cell lymphoma (NKTCL) exhibits highly aggressive clinical behavior, and the outcomes for relapsed/refractory patients are still poor. Recently, the mechanism underlying the effect of Epstein-Barr virus (EBV) infection, which has not been fully defined in NKTCL, has attracted great attention. We explored how LMP1 promoted aerobic glycolysis via metabolic sequencing combined with mRNA sequencing and immunoprecipitation coupled to mass spectrometry. Experimental assays were used to determine the effects of LMP1 and its downstream pathway on the function and glucose metabolism of NKTCL cells. The correlations between LMP1 expression in patients and their clinical features, treatment response, and prognosis were analyzed. Results show that LMP1 enhances NKTCL cell proliferation in vitro and in vivo, inhibits apoptosis, and decreases gemcitabine sensitivity. In addition, LMP1 also enhances aerobic glycolysis in NKTCL cells, as indicated by increases in glucose uptake, lactate production, and extracellular acidification rate. Clinically, LMP1 expression is correlated with risk stratification, treatment response, and prognosis, and higher LMP1 expression indicates greater SUVmax for NKTCL patients. Mechanistically, LMP1 competitively binds to TRAF3 to promote cell proliferation and aerobic glycolysis by regulating the noncanonical NF-κB pathway. The application of an NF-κB pathway inhibitor or reactivation of the NF-κB pathway affects aerobic glycolysis and the biological function of NKTCL cells. In summary, this study is the first to describe and define in detail how LMP1 affects glucose metabolism in NKTCL and might provide a novel perspective for further treatment.
自然杀伤/T 细胞淋巴瘤（NKTCL）表现出高度侵袭性的临床行为，复发/难治患者的预后仍然较差。最近，EB 病毒（EBV）感染的作用机制在 NKTCL 中尚未完全明确，引起了极大关注。我们通过代谢测序结合 mRNA 测序和免疫沉淀结合质谱探索了 LMP1 如何通过代谢促进有氧糖酵解。实验检测用于确定 LMP1 及其下游途径对 NKTCL 细胞功能和葡萄糖代谢的影响。分析了 LMP1 在患者中的表达与其临床特征、治疗反应和预后之间的相关性。结果表明，LMP1 增强了 NKTCL 细胞的体外和体内增殖，抑制了凋亡，并降低了吉西他滨的敏感性。此外，LMP1 还增强了 NKTCL 细胞的有氧糖酵解，表现为葡萄糖摄取、乳酸生成和细胞外酸化率增加。临床上，LMP1 的表达与风险分层、治疗反应和预后相关，LMP1 表达水平越高，NKTCL 患者的 SUVmax 值越高。从机制上讲，LMP1 竞争性地与 TRAF3 结合，通过调节非经典 NF-κB 通路促进细胞增殖和有氧糖酵解。NF-κB 通路抑制剂的应用或 NF-κB 通路的再激活会影响有氧糖酵解和 NKTCL 细胞的生物学功能。总之，本研究首次描述并详细定义了 LMP1 如何影响 NKTCL 中的葡萄糖代谢，并可能为进一步治疗提供新视角。
