Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action
Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action
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DOI：
10.1038/sj.onc.1208045
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发表时间：
2004-10-28
期刊：
影响因子：
8
通讯作者：
Lacal, JC
中科院分区：
文献类型：
--
作者：
Rodríguez-González, A;de Molina, AR;Lacal, JC
胆碱激酶（ChoK，E. C. 2.7.1.32）参与磷脂酰胆碱（PC）的合成，并且已经发现在人肿瘤和肿瘤衍生的细胞系中增加。此外，已报道ChoK抑制剂在体外和体内均显示出有效的和选择性的抗肿瘤活性。在这里，我们提供了一个合理的理解ChoK抑制剂的抗肿瘤活性的基础。在正常细胞中，通过抑制ChoK来阻断磷酸胆碱（PCo）的从头合成，促进pRb的去磷酸化，导致可逆的细胞周期停滞在G 0/G1期。相比之下，肿瘤细胞中的ChoK抑制使细胞不能停滞在G 0/G1期，这表现为缺乏pRb去磷酸化。此外，肿瘤细胞特别遭受主要膜脂质PC和鞘磷脂（SM）代谢的剧烈摆动。这种脂质破坏导致神经酰胺的细胞内水平的扩大。因此，正常细胞不受影响，但肿瘤细胞被促进凋亡。因此，我们在本研究中提供了ChoK抑制剂潜在临床应用的基本原理。
Choline kinase (ChoK, E. C. 2.7.1.32) is involved in the synthesis of phosphatidylcholine ( PC), and has been found to be increased in human tumors and tumor-derived cell lines. Furthermore, ChoK inhibitors have been reported to show a potent and selective antitumoral activity both in vitro and in vivo. Here, we provide the basis for a rational understanding of the antitumoral activity of ChoK inhibitors. In normal cells, blockage of de novo phosphorylcholine (PCho) synthesis by inhibition of ChoK promotes the dephosphorylation of pRb, resulting in a reversible cell cycle arrest at G0/G1 phase. In contrast, ChoK inhibition in tumor cells renders cells unable to arrest in G0/G1 as manifested by a lack of pRb dephosphorylation. Furthermore, tumor cells specifically suffer a drastic wobble in the metabolism of main membrane lipids PC and sphingomyelin (SM). This lipid disruption results in the enlargement of the intracellular levels of ceramides. As a consequence, normal cells remain unaffected, but tumor cells are promoted to apoptosis. Thus, we provide in this study the rationale for the potential clinical use of ChoK inhibitors.