Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells.
Cancer treatment is in the need of selective drugs that can interfere specifically with signalling pathways affected during the carcinogenic process. Identification of new potential molecular targets is the key event in the design of new anticancer strategies. Once identified, attempts for the generation of specific molecules to regulate their function can be achieved. The relevance of deregulation of choline kinase (ChoK, E.C. 2.7.1.32) in oncogene-driven cell transformation has been previously demonstrated. Here we provide strong evidence that MN58b, a selective inhibitor of ChoK, is rather specific to this enzyme, with no effect on a variety of oncogene-activated signalling pathways involved in the regulation of cell proliferation. MN58b does not affect MAPKs, PI3K, and other enzymes involved in the regulation of phospholipid metabolism such as phospholipases C, D, and A2, CTP:phosphocholine cytidylyltransferase, or diacylglycerol choline-phosphotransferase. Consistent with this specificity, ectopic expression of ChoK resulted in resistance to its inhibitor. Finally, nontransformed cells were able to resume cell proliferation after removal of the drug, while transformed cells were irreversibly affected. These results indicate that inhibition of ChoK is a rather specific strategy for the cytotoxic treatment of transformed cells.
Rodríguez-González
Agustín
A
Department of Molecular and Cellular Biology of Cancer, Instituto de Investigaciones Biomédicas (CSIC), Arturo Duperier 4, Madrid 28029, Spain.
Ramírez de Molina
Ana
A
Fernández
Félix
F
Ramos
Maria Angeles
MA
del Carmen Núñez
Maria
M
Campos
Joaquín
J
Lacal
Juan Carlos
JC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D006426:Hemicholinium 3 / Q000031:analogs & derivatives*; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D006426:Hemicholinium 3; D002797:Choline Kinase