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http://hdl.handle.net/10261/109521
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dc.contributor.author | Sánchez-López, E. | - |
dc.contributor.author | Zimmerman, T. | - |
dc.contributor.author | Gómez del Pulgar, Teresa | - |
dc.contributor.author | Moyer, M.P. | - |
dc.contributor.author | Lacal, Juan Carlos | - |
dc.contributor.author | Cebrián, Arancha | - |
dc.date.accessioned | 2015-01-20T09:58:27Z | - |
dc.date.available | 2015-01-20T09:58:27Z | - |
dc.date.issued | 2013-11-28 | - |
dc.identifier.citation | Cell Death and Disease (2013) 4, e933 | es_ES |
dc.identifier.issn | 2041-4889 | - |
dc.identifier.uri | http://hdl.handle.net/10261/109521 | - |
dc.description | 11 p.-6 fig. | es_ES |
dc.description.abstract | Endoplasmic reticulum (ER) is a central organelle in eukaryotic cells that regulates protein synthesis and maturation.Perturbation of ER functions leads to ER stress, which has been previously associated with a broad variety of diseases. ER stress is generally regarded as compensatory, but prolonged ER stress has been involved in apoptosis induced by several cytotoxic agents. Choline kinase a (ChoKa), the first enzyme in the Kennedy pathway, is responsible for the generation of phosphorylcholine (PCho) that ultimately renders phosphatidylcholine. ChoKa overexpression and high PCho levels have been detected in several cancer types. Inhibition of ChoKa has demonstrated antiproliferative and antitumor properties; however, the mechanisms underlying these activities remain poorly understood. Here, we demonstrate that ChoKa inhibitors (ChoKIs), MN58b and RSM932A, induce cell death in cancer cells (T47D,MCF7, MDA-MB231, SW620 and H460), through the prolonged activation of ER stress response. Evidence of ChoKIs-induced ER stress includes enhanced production of glucose-regulated protein, 78 kDa (GRP78), protein disulfide isomerase, IRE1a, CHOP, CCAAT/enhancer-binding protein beta (C/EBPb) and TRB3. Although partial reduction of ChoKa levels by small interfering RNA was not sufficient to increase the production of ER stress proteins, silencing of ChoKa levels also show a decrease in CHOP overproduction induced by ChoKIs, which suggests that ER stress induction is due to a change in ChoKa protein folding after binding to ChoKIs. Silencing of CHOP expression leads to a reduction in C/EBPb, ATF3 and GRP78 protein levels and abrogates apoptosis in tumor cells after treatment with ChoKIs, suggesting that CHOP maintains ER stress responses and triggers the pro-apoptotic signal. Consistent with the differential effect of ChoKIs in cancer and primary cells previously described, ChoKIs only promoted a transient and moderated ER stress response in the non-tumorogenic cells MCF10A. In conclusion, pharmacological inhibition of ChoKa induces cancer cell death through a mechanism that involves the activation of exaggerated and persistent ER stress supported by CHOP overproduction. | es_ES |
dc.description.sponsorship | This work has been funded by the following grants:Comunidad de Madrid (S2010/BMD-2326), Ministerio de Economía y Competitividad (SAF2011-29699, RD06-0020-0016 and RD12/0036/0019) and EU no.259737. ESL is a Sara Borell fellow under the program ISCIII/MICINN. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.relation.isversionof | Publisher's version | es_ES |
dc.rights | openAccess | es_ES |
dc.title | Choline kinase inhibition induces exacerbated endoplasmic reticulum stress and triggers apoptosis via CHOP in cancer cells | es_ES |
dc.type | artículo | es_ES |
dc.identifier.doi | 10.1038/cddis.2013.453 | - |
dc.description.peerreviewed | Peer reviewed | es_ES |
dc.relation.publisherversion | http://dx.doi.org/10.1038/cddis.2013.453 | - |
dc.identifier.e-issn | 2041-4889 | - |
dc.rights.license | http://creativecommons.org/licenses/by-nc/3.0/ | es_ES |
dc.relation.csic | Sí | es_ES |
dc.identifier.pmid | 24287694 | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.cerifentitytype | Publications | - |
item.languageiso639-1 | en | - |
item.grantfulltext | open | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | With Fulltext | - |
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cddis2013. T. Zimmerman.pdf | 1,8 MB | Adobe PDF | Visualizar/Abrir |
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