Choline Kinase Alpha Depletion Selectively Kills Tumoral Cells
Monica Banez-Coronel, Ana Ramirez de Molina, Agustin Rodriguez-Gonzalez, Jacinto Sarmentero, Mª Angeles Ramos, Miguel Angel Garcia-Cabezas, Lourdes Garcia-Oroz and Juan Carlos Lacal
Affiliation: Centro Nacional de Biotecnologia, C/ Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain.
Keywords: Choline Kinase, anticancer drugs, target validation, apoptosis, ChoK Inhibitors, shRNA
Choline Kinase (ChoK) comprises a family of cytosolic enzymes involved in the synthesis of phosphatidylcholine (PC), the most abundant phospholipid in eukaryotic cell membranes. One of the ChoK isoforms, Choline Kinase α (ChoKα), is found over expressed in human tumours. Chemical inhibitors able to interfere with ChoK activity have proven to be effective antitumoral drugs in vitro and in vivo. To validate the use of selective ChoKα inhibitors in cancer therapy, we have developed a genetic strategy to interfere specifically with ChoKα activity based on the generation of a shRNA against the alpha isoform of ChoK. Here we demonstrate that specific inhibition of ChoKα by shRNA has antitumor activity. The specific depletion of ChoKα induces apoptosis in several tumor-derived cell lines from breast, bladder, lung and cervix carcinoma tumors, while the viability of normal primary cells is not affected. Furthermore, this selective antiproliferative effect is achieved both under in vitro and in vivo conditions, as demonstrated by an inducible ChoKα suppression system in human tumour xenografts. These results demonstrate that ChoKα inhibition is a useful antitumoral strategy per se, and provides definitive and non-ambiguous evidence that ChoKα can be used as an efficient and selective drug target for cancer therapy.
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