文章：

T细胞淋巴瘤中胆碱代谢失调：胆碱激酶-α的作用和治疗靶向

Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting

原文发布日期：2015-03-13

DOI: 10.1038/bcj.2015.10

类型: Original Article

开放获取: 是

英文摘要：

Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways.

摘要翻译： 

癌细胞具有独特的代谢组学特征。代谢酶通过调控关键致癌信号通路在肿瘤进展中发挥重要作用。本研究对45例T细胞淋巴瘤患者及50名健康志愿者进行血清代谢组学分析，结果显示T细胞淋巴瘤中存在胆碱代谢紊乱，该现象与肿瘤细胞过度表达胆碱激酶α相关。在T淋巴细胞瘤细胞中，通过药理学及分子沉默手段抑制胆碱激酶α后，可显著降低Ras-GTP活性、减少AKT与ERK磷酸化并下调MYC癌蛋白表达，从而恢复胆碱代谢物水平并诱导肿瘤细胞发生凋亡/坏死性凋亡。在T淋巴细胞瘤异种移植小鼠模型中，胆碱激酶α抑制剂CK37能显著延缓肿瘤生长，抑制Ras-AKT/ERK信号通路，提升溶血磷脂酰胆碱水平，并诱导原位细胞凋亡/坏死性凋亡。综上，作为胆碱代谢异常的关键调控基因，胆碱激酶α具有致癌活性，不仅是T细胞淋巴瘤的潜在治疗靶点，也对Ras信号通路异常的其他血液系统恶性肿瘤具有治疗价值。

原文链接：

Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting