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 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.
Keywords: Choline Kinase, anticancer drugs, target validation, apoptosis, ChoK Inhibitors, shRNA
Current Cancer Drug Targets
Title: Choline Kinase Alpha Depletion Selectively Kills Tumoral Cells
Volume: 8 Issue: 8
Author(s): 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:
Keywords: Choline Kinase, anticancer drugs, target validation, apoptosis, ChoK Inhibitors, shRNA
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 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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Banez-Coronel Monica, de Molina Ramirez Ana, Rodriguez-Gonzalez Agustin, Sarmentero Jacinto, Ramos Angeles Mª, Garcia-Cabezas Angel Miguel, Garcia-Oroz Lourdes and Lacal Carlos Juan, Choline Kinase Alpha Depletion Selectively Kills Tumoral Cells, Current Cancer Drug Targets 2008; 8 (8) . https://dx.doi.org/10.2174/156800908786733432
DOI https://dx.doi.org/10.2174/156800908786733432 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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