Abstract
BackgroundThe 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 ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα 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 ChoKβ in carcinogenesis has been reported.Methodology/Principal FindingsHere we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ 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 ChoKβ display an ethanolamine kinase role, ChoKα1 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 ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ 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 ChoKα1 than ChoKβ.Conclusion/SignificanceThis study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ 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.
Highlights
Human choline kinase alpha (ChoKa) and beta (ChoKb) are members of the choline kinase family
The family of human choline/ethanolamine kinases comprises two genes, CHKA and CHKB that codify for three enzymes, ChoKa1 (52 kDa), ChoKa2 (50 kDa) and ChoKb1 (45 kDa)
ChoKa1 and ChoKa2 are almost identical, except for a stretch of 18 extra amino acids in ChoKa1, as they result from differential splicing from the same gene, CHKA
Summary
Human choline kinase alpha (ChoKa) and beta (ChoKb) are members of the choline kinase family. In mammals this family is encoded by two separate genes, CHKA and CHKB, resulting in three different proteins with a choline/ethanolamine kinase (ChoK/EtnK) domain: ChoKa1 (NP_001268), ChoKa2 (NP_997634) and ChoKb1 (NP_005189) [1]. The presence of the ChoK/EtnK domain confers the capacity to catalyze the phosphorylation of choline (Cho) to phosphocholine (PCho) [1]. This constitutes the first step in the biosynthesis pathway of phosphatidylcholine (PC) [2]. No evidence for a role of ChoKb in carcinogenesis has been reported
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