Abstract
Cancer treatment is in the need of selective drugs that can interfere specifically with signalling pathways affected during the carcinogenic process. Identification of new potential molecular targets is the key event in the design of new anticancer strategies. Once identified, attempts for the generation of specific molecules to regulate their function can be achieved. The relevance of deregulation of choline kinase (ChoK, E.C. 2.7.1.32) in oncogene-driven cell transformation has been previously demonstrated. Here we provide strong evidence that MN58b, a selective inhibitor of ChoK, is rather specific to this enzyme, with no effect on a variety of oncogene-activated signalling pathways involved in the regulation of cell proliferation. MN58b does not affect MAPKs, PI3K, and other enzymes involved in the regulation of phospholipid metabolism such as phospholipases C, D, and A2, CTP:phosphocholine cytidylyltransferase, or diacylglycerol choline-phosphotransferase. Consistent with this specificity, ectopic expression of ChoK resulted in resistance to its inhibitor. Finally, nontransformed cells were able to resume cell proliferation after removal of the drug, while transformed cells were irreversibly affected. These results indicate that inhibition of ChoK is a rather specific strategy for the cytotoxic treatment of transformed cells.
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Acknowledgements
We thank Drs MA Gallo and A Espinosa for helpful discussions. This work was supported by Grants 2FD1997-1569 and SAF2001-2042 from MCYT and Grants FIS03-C03/10 and FIS03-C03/08, from MSyC. AR-G is a fellow from Gobierno Vasco, Grant (ref: BFI98.124). ARM is a fellow from Fondo de Investigación Sanitaria (Instituto de Salud Carlos III), Grant BEFI 99/9125 (ref: CPC/CLC).
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Rodríguez-González, A., de Molina, A., Fernández, F. et al. Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells. Oncogene 22, 8803–8812 (2003). https://doi.org/10.1038/sj.onc.1207062
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DOI: https://doi.org/10.1038/sj.onc.1207062
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