Journal
CURRENT CANCER DRUG TARGETS
Volume 8, Issue 8, Pages 709-719Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156800908786733432
Keywords
Choline Kinase; anticancer drugs; target validation; apoptosis; ChoK Inhibitors; shRNA
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Funding
- Comunidad de Madrid [GR-SAL-0821-2004]
- Ministerio de Educacion y Ciencia [SAF2004-0577, SAF2005-06195-C02-01]
- Ministerio de Sanidad (RTICC)
- Fundacion Mutua Madrilena
- EU [LSHG-CT-2006-037278]
- TCD Pharma
- ARM from Fundacion Mutua Madrilena
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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 a (ChoK alpha), 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 ChoK alpha inhibitors in cancer therapy, we have developed a genetic strategy to interfere specifically with ChoK alpha activity based on the generation of a shRNA against the alpha isoform of ChoK. Here we demonstrate that specific inhibition of ChoK alpha by shRNA has antitumor activity. The specific depletion of ChoK alpha 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 ChoK alpha suppression system in human tumour xenografts. These results demonstrate that ChoK alpha inhibition is a useful antitumoral strategy per se, and provides definitive and non-ambiguous evidence that ChoK alpha can be used as an efficient and selective drug target for cancer therapy.
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