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Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action

Oncogene volume 23, pages 8247–8259 (2004)Cite this article

Abstract

Choline kinase (ChoK, E.C. 2.7.1.32) is involved in the synthesis of phosphatidylcholine (PC), and has been found to be increased in human tumors and tumor-derived cell lines. Furthermore, ChoK inhibitors have been reported to show a potent and selective antitumoral activity both in vitro and in vivo. Here, we provide the basis for a rational understanding of the antitumoral activity of ChoK inhibitors. In normal cells, blockage of de novo phosphorylcholine (PCho) synthesis by inhibition of ChoK promotes the dephosphorylation of pRb, resulting in a reversible cell cycle arrest at G0/G1 phase. In contrast, ChoK inhibition in tumor cells renders cells unable to arrest in G0/G1 as manifested by a lack of pRb dephosphorylation. Furthermore, tumor cells specifically suffer a drastic wobble in the metabolism of main membrane lipids PC and sphingomyelin (SM). This lipid disruption results in the enlargement of the intracellular levels of ceramides. As a consequence, normal cells remain unaffected, but tumor cells are promoted to apoptosis. Thus, we provide in this study the rationale for the potential clinical use of ChoK inhibitors.

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Acknowledgements

This work was supported by Grant SAF2001-2042 from MCyT, and by Grants FIS C03-08 and C03-10 from MSyC. ARG was a fellow from Departamento de Educación (Universidades e Investigación del Gobierno Vasco), Grant [Ref. BFI (98.124)]. ARM was a fellow from FIS (Instituto de Salud Carlos III), Grant BEFI 99/9125 (Ref. CPC/CLC).

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  1. Department of Molecular and Cellular Biology of Cancer, Translational Oncology Unit, Instituto de Investigaciones Biomédicas, CSIC, Arturo Duperier 4, Madrid, 28029, Spain

    Agustín Rodríguez-González, Ana Ramirez de Molina, Felix Fernández & Juan Carlos Lacal

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  1. Agustín Rodríguez-González
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  2. Ana Ramirez de Molina
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  3. Felix Fernández
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  4. Juan Carlos Lacal
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Correspondence to Juan Carlos Lacal.

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Rodríguez-González, A., Ramirez de Molina, A., Fernández, F. et al. Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action. Oncogene 23, 8247–8259 (2004). https://doi.org/10.1038/sj.onc.1208045

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