title: Choline kinase alpha depletion selectively kills tumoral cells.
abstract: 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 alpha (ChoKalpha), 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 ChoKalpha inhibitors in cancer therapy, we have developed a genetic strategy to interfere specifically with ChoKalpha activity based on the generation of a shRNA against the alpha isoform of ChoK. Here we demonstrate that specific inhibition of ChoKalpha by shRNA has antitumor activity. The specific depletion of ChoKalpha 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 ChoKalpha suppression system in human tumour xenografts. These results demonstrate that ChoKalpha inhibition is a useful antitumoral strategy per se, and provides definitive and non-ambiguous evidence that ChoKalpha can be used as an efficient and selective drug target for cancer therapy.
authors.affiliation: Translational Oncology Unit CSIC-UAM-La Paz, Instituto de Investigaciones Biomédicas, Centro Nacional de Biotecnología, Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bañez-Coronel
authors.forename: Ana
authors.initials: A
authors.lastname: Ramírez de Molina
authors.forename: Agustín
authors.initials: A
authors.lastname: Rodríguez-González
authors.forename: Jacinto
authors.initials: J
authors.lastname: Sarmentero
authors.forename: Ma Angeles
authors.initials: MA
authors.lastname: Ramos
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: García-Cabezas
authors.forename: Lourdes
authors.initials: L
authors.lastname: García-Oroz
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Lacal
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002797:Choline Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017931:DNA Primers; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D008856:Microscopy, Fluorescence; D012313:RNA / Q000235:genetics; D034622:RNA Interference
chemical_list: D017931:DNA Primers; D012313:RNA; C517212:CHKA protein, human; D002797:Choline Kinase