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 (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.
Rodríguez-González
Agustín
A
Translational Oncology Unit, Department of Molecular and Cellular Biology of Cancer, Instituto de Investigaciones Biomédicas, CSIC, Arturo Duperier 4, 28029 Madrid, Spain.
Ramirez de Molina
Ana
A
Fernández
Felix
F
Lacal
Juan Carlos
JC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism*; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase; D006801:Humans; D010743:Phospholipids / Q000378:metabolism; D016196:S Phase
D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D010743:Phospholipids; D002797:Choline Kinase