Inhibition of ChoK is an efficient antitumor strategy for Harvey-, Kirsten-, and N-ras-transformed cells.
An increasing amount of evidence suggests that elevated PCho levels are related to the transforming properties of the H-Ras oncoprotein. Based on these observations, we have designed an antitumor strategy using choline kinase, the enzyme responsible of PCho production, as a novel target for drug discovery. However, little relationship between this lipid-related pathway and the other two Ras members, N- and K-ras, has been established. Since N- and K-ras are the most frequently mutated ras genes in human tumors, we have analyzed the PC-PLD/ChoK pathway and the sensitivity to ChoK inhibition of all three ras-transformed cells. Here we demonstrate that transformation by the three Ras oncoproteins results in increased levels of PCho to a similar extent, resulting from a similar constitutive increase of ChoK activity. As well, sensitivity to choline kinase inhibitors as antiproliferative drugs is similar in cell lines transformed by each of the three ras oncogenes, being in all cases higher than parental, nontransformed cells. In addition, H, K and N-ras-induced alterations in PC metabolism is discussed. These results indicate that ChoK can be used as a general target for anticancer drug design against Ras-dependent tumorigenesis.
Ramírez de Molina
A
A
Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain.
Rodríguez-González
A
A
Penalva
V
V
Lucas
L
L
Lacal
J C
JC
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras; D051379:Mice; D010739:Phospholipase D / Q000032:analysis
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D002797:Choline Kinase; D010739:Phospholipase D; D002794:Choline