Anticancer Activity of the Choline Kinase Inhibitor PL48 Is Due to Selective Disruption of Choline Metabolism and Transport Systems in Cancer Cell Lines
Pablo García-Molina,
Alberto Sola-Leyva,
Pilar M. Luque-Navarro,
Alejandro Laso,
Pablo Ríos-Marco,
Antonio Ríos,
Daniela Lanari,
Archimede Torretta,
Emilio Parisini,
Luisa C. López-Cara,
Carmen Marco,
María P. Carrasco-Jiménez
Affiliations
Pablo García-Molina
Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
Alberto Sola-Leyva
Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
Pilar M. Luque-Navarro
Department of Pharmaceutical and Organic Chemistry, University of Granada, 18071 Granada, Spain
Alejandro Laso
Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
Pablo Ríos-Marco
Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
Antonio Ríos
Department of Cell Biology, University of Granada, 18071 Granada, Spain
Daniela Lanari
Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
Archimede Torretta
Center for Nano Science and Technology @Polimi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, 20133 Milano, Italy
Emilio Parisini
Center for Nano Science and Technology @Polimi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, 20133 Milano, Italy
Luisa C. López-Cara
Department of Pharmaceutical and Organic Chemistry, University of Granada, 18071 Granada, Spain
Carmen Marco
Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
María P. Carrasco-Jiménez
Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain
A large number of different types of cancer have been shown to be associated with an abnormal metabolism of phosphatidylcholine (PC), the main component of eukaryotic cell membranes. Indeed, the overexpression of choline kinase α1 (ChoKα1), the enzyme that catalyses the bioconversion of choline to phosphocholine (PCho), has been found to associate with cell proliferation, oncogenic transformation and carcinogenesis. Hence, ChoKα1 has been described as a possible cancer therapeutic target. Moreover, the choline transporter CTL1 has been shown to be highly expressed in several tumour cell lines. In the present work, we evaluate the antiproliferative effect of PL48, a rationally designed inhibitor of ChoKα1, in MCF7 and HepG2 cell lines. In addition, we illustrate that the predominant mechanism of cellular choline uptake in these cells is mediated by the CTL1 choline transporter. A possible correlation between the inhibition of both choline uptake and ChoKα1 activity and cell proliferation in cancer cell lines is also highlighted. We conclude that the efficacy of this inhibitor on cell proliferation in both cell lines is closely correlated with its capability to block choline uptake and ChoKα1 activity, making both proteins potential targets in cancer therapy.
