Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: implications in cancer onset and treatment.
BACKGROUND
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 ChoKalpha and ChoKbeta isoforms, the first one with two different variants of splicing. Recently ChoKalpha 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 ChoKbeta in carcinogenesis has been reported.


RESULTS
Here we compare the in vitro and in vivo properties of ChoKalpha1 and ChoKbeta in lipid metabolism, and their potential role in carcinogenesis. Both ChoKalpha1 and ChoKbeta 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 ChoKbeta display an ethanolamine kinase role, ChoKalpha1 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 ChoKalpha1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKbeta overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKalpha1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKbeta 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 ChoKalpha1 than ChoKbeta.


CONCLUSIONS
This study represents the first evidence of the distinct metabolic role of ChoKalpha and ChoKbeta 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.
Gallego-Ortega
David
D
Translational Oncology Unit, CSIC-UAM-La Paz, Instituto de Investigaciones Biomédicas, Madrid, Spain.
Ramirez de Molina
Ana
A
Ramos
Maria Angeles
MA
Valdes-Mora
Fatima
F
Barderas
Maria Gonzalez
MG
Sarmentero-Estrada
Jacinto
J
Lacal
Juan Carlos
JC
D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002797:Choline Kinase / Q000378:metabolism / Q000502:physiology*; D004285:Dogs; D004983:Ethanolamines / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D050356:Lipid Metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D010767:Phosphorylcholine / Q000737:chemistry; D020033:Protein Isoforms
D004983:Ethanolamines; D020033:Protein Isoforms; D010767:Phosphorylcholine; C005448:phosphorylethanolamine; D002797:Choline Kinase