Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: implications in cancer onset and treatment.
Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: implications in cancer onset and treatment.
复制标题
DOI：
10.1371/journal.pone.0007819
复制
发表时间：
2009-11-12
期刊：
影响因子：
3.7
通讯作者：
Lacal JC
中科院分区：
文献类型：
--
作者：
Gallego-Ortega D;Ramirez de Molina A;Ramos MA;Valdes-Mora F;Barderas MG;Sarmentero-Estrada J;Lacal JC
肯尼迪途径通过其两个分支产生磷酸胆碱和磷酸乙醇胺。胆碱激酶（Choline Kinase，ChoK）是合成磷酸胆碱的肯尼迪分支的第一个酶，磷酸胆碱是质膜的主要成分。ChoK家族蛋白由ChoKα和ChoKβ两种异构体组成，其中第一种具有两种不同的剪接变体。最近，ChoKα被认为与致癌过程有关，因为它在多种人类癌症中过度表达。然而，没有证据表明ChoKβ在致癌作用中的作用。本文比较了ChoKα1和ChoKβ在脂质代谢中的体外和体内特性，以及它们在致癌中的潜在作用。ChoKα1和ChoKβ在细胞提取物中均表现出胆碱和乙醇胺激酶活性，但对底物的亲和力不同。然而，当在全细胞中过表达时，它们的行为不同。而ChoKβ显示乙醇胺激酶的作用，ChoKα1提出了双重胆碱/乙醇胺激酶的作用，这表明在体内条件下，在不同的生化途径的每个ChoK亚型的参与。此外，虽然ChoKα1的过表达在HEK 293 T或MDCK细胞中过表达时是致癌的，但ChoKβ的过表达不足以诱导体外细胞转化或体内肿瘤生长。此外，在一组乳腺癌和肺癌细胞系中发现ChoKα1 mRNA水平显著上调，但未观察到ChoKβ mRNA水平的变化。最后，先前描述的具有体内抗肿瘤活性的ChoK的有效抑制剂MN 58 b显示出比ChoKβ高20倍以上的对ChoKα1的效率。这项研究首次证明了ChoKα和ChoKβ亚型具有不同的代谢作用，表明它们在人类致癌过程中具有不同的生理作用和意义。这些发现构成了基于ChoK抑制的抗肿瘤策略设计的一个进步。
The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.
登录
查看更多内容
影响因子：
4.1
作者：
Aoyama, C;Ohtani, A;Ishidate, K
通讯作者：
Ishidate, K
影响因子：
4
作者：
CARNERO, A;LACAL, JC
通讯作者：
LACAL, JC
影响因子：
6.4
作者：
Eliyahu, Galit;Kreizman, Tamar;Degani, Hadassa
通讯作者：
Degani, Hadassa
影响因子：
11.2
作者：
Krishnamachary B;Glunde K;Wildes F;Mori N;Takagi T;Raman V;Bhujwalla ZM
通讯作者：
Bhujwalla ZM
影响因子：
11.2
作者：
Al-Saffar, NMS;Troy, H;Chung, YL
通讯作者：
Chung, YL