English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/123932
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
Exportar a otros formatos:


EIF2 kinases mediate β-lapachone toxicity in yeast and human cancer cells

AuthorsMenacho-Márquez, Mauricio ; Rodríguez-Hernández, Carlos J.; Villaronga, M. A.; Pérez-Valle, Jorge ; Gadea Vacas, José ; Belandia, Borja ; Murguía, José Ramón
KeywordsAntitumoral drug
DNA damage
Integrated stress response
Reactive oxygen species
Issue Date15-Feb-2015
PublisherTaylor & Francis
Landes Bioscience
CitationCell Cycle 14(4): 630-640 (2015)
Abstractβ-lapachone (β-lap) is a novel anticancer agent that selectively induces cell death in human cancer cells, by activation of the NQO1 NAD(P)H dehydrogenase and radical oxygen species (ROS) generation. We characterized the gene expression profile of budding yeast cells treated with β-lap using cDNA microarrays. Genes involved in tolerance to oxidative stress were differentially expressed in bβ-lap treated cells. β-lap treatment generated reactive oxygen species (ROS), which were efficiently blocked by dicoumarol, an inhibitor of NADH dehydrogenases. A yeast mutant in the mitocondrial NADH dehydrogenase Nde2p was found to be resistant to β-lap treatment, despite inducing ROS production in a WT manner. Most interestingly, DNA damage responses triggered by β-lap were abolished in the nde2D mutant. Amino acid biosynthesis genes were also induced in β-lap treated cells, suggesting that β-lap exposure somehow triggered the General Control of Nutrients (GCN) pathway. Accordingly, β-lap treatment increased phosphorylation of eIF2α subunit in a manner dependent on the Gcn2p kinase. eIF2α phosphorylation required Gcn1p, Gcn20p and Nde2p. Gcn2p was also required for cell survival upon exposure to β-lap and to elicit checkpoint responses. Remarkably, β-lap treatment increased phosphorylation of eIF2α in breast tumor cells, in a manner dependent on the Nde2p ortholog AIF, and the eIF2 kinase PERK. These findings uncover a new target pathway of β-lap in yeast and human cells and highlight a previously unknown functional connection between Nde2p, Gcn2p and DNA damage responses.
Publisher version (URL)http://dx.doi.org/10.4161/15384101.2014.994904
Identifiersdoi: 10.4161/15384101.2014.994904
issn: 1551-4005
Appears in Collections:(IBMCP) Artículos
(IBMB) Artículos
(IIBM) Artículos
Files in This Item:
File Description SizeFormat 
accesoRestringido.pdf15,38 kBAdobe PDFThumbnail
Show full item record
Review this work

Related articles:

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