English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/109521
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE
Exportar a otros formatos:


Choline kinase inhibition induces exacerbated endoplasmic reticulum stress and triggers apoptosis via CHOP in cancer cells

AuthorsSánchez-López, E.; Zimmerman, T.; Gómez del Pulgar, Teresa; Moyer, M.P.; Lacal, Juan Carlos ; Cebrián, Arancha
Issue Date28-Nov-2013
PublisherNature Publishing Group
CitationCell Death and Disease (2013) 4, e933
AbstractEndoplasmic 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.
Description11 p.-6 fig.
Publisher version (URL)http://dx.doi.org/10.1038/cddis.2013.453
Appears in Collections:(CIB) Artículos
Files in This Item:
File Description SizeFormat 
cddis2013. T. Zimmerman.pdf1,8 MBAdobe PDFThumbnail
Show full item record
Review this work

WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.