Choline kinase alpha depletion selectively kills tumoral cells.
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.
Bañez-Coronel
Mónica
M
Translational Oncology Unit CSIC-UAM-La Paz, Instituto de Investigaciones Biomédicas, Centro Nacional de Biotecnología, Madrid, Spain.
Ramírez de Molina
Ana
A
Rodríguez-González
Agustín
A
Sarmentero
Jacinto
J
Ramos
Ma Angeles
MA
García-Cabezas
Miguel Angel
MA
García-Oroz
Lourdes
L
Lacal
Juan Carlos
JC
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
D017931:DNA Primers; D012313:RNA; C517212:CHKA protein, human; D002797:Choline Kinase