title: A non-catalytic role of choline kinase alpha is important  in promoting cancer cell survival.
abstract: Choline kinase alpha (ChoKα) is regarded as an attractive cancer target. The enzyme catalyses the formation of phosphocholine(PCho), an important precursor in the generation of phospholipids essential for cell growth. ChoKα has oncogenic properties and is critical for the survival of cancer cells. Overexpression of the ChoKα protein can transform noncancer cells into cells with a cancerous phenotype, and depletion of the ChoKα protein can result in cancer cell death. However, the mechanisms underlying the tumourigenic properties of ChoKα are not fully understood. ChoKα was recently demonstrated to associate with other oncogenic proteins, raising the possibility that a non-catalytic protein scaffolding function drives the tumourigenic properties of ChoKα rather than a catalytic function. In order to differentiate these two roles, we compared the impact on cancer cell survival using two tools specific for ChoKα: (1) small interfering RNA (siRNA) to knockdown the ChoKα protein levels; and (2) compound V-11-0711, a novel potent and selective ChoKα inhibitor (ChoKα IC50 20 nM), to impede the catalytic activity. Both treatments targeted the endogenous ChoKα protein in HeLa cells, as demonstrated by a substantial reduction in the PCho levels. siRNA knockdown of the ChoKα protein in HeLa cells resulted in significant cell death through apoptosis. In contrast, compound V-11-0711 caused a reversible growth arrest. This suggests that inhibition of ChoKα catalytic activity alone is not sufficient to kill cancer cells, and leads us to conclude that there is a role for the ChoKα protein in promoting cancer cell survival that is independent of its catalytic activity.
authors.forename: S C
authors.initials: SC
authors.lastname: Falcon
authors.forename: C S
authors.initials: CS
authors.lastname: Hudson
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: M
authors.initials: M
authors.lastname: Mortimore
authors.forename: J M
authors.initials: JM
authors.lastname: Golec
authors.forename: P A
authors.initials: PA
authors.lastname: Charlton
authors.forename: P
authors.initials: P
authors.lastname: Weber
authors.forename: H
authors.initials: H
authors.lastname: Sundaram
mesh_terms: D002470:Cell Survival / Q000502:physiology*; D002797:Choline Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000503:physiopathology; D010767:Phosphorylcholine / Q000378:metabolism*; D034741:RNA, Small Interfering
chemical_list: D034741:RNA, Small Interfering; D010767:Phosphorylcholine; C517212:CHKA protein, human; D002797:Choline Kinase
keywords: choline kinase alpha; apoptosis; scaffolding; inhibitor; siRNA