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The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53-Independent Manner in Colon and Breast Cancer Cells

dc.contributor.authorGarcia, María Angel
dc.contributor.authorCarrasco, Esther
dc.contributor.authorAguilera, Margarita
dc.contributor.authorAlvarez, Pablo
dc.contributor.authorRivas, Carmen
dc.contributor.authorCampos, Joaquín Maria
dc.contributor.authorPrados, José Carlos
dc.contributor.authorCalleja, Miguel Angel
dc.contributor.authorEsteban, Mariano
dc.contributor.authorMarchal, Juan Antonio
dc.contributor.authorAranega, Antonia
dc.contributor.authoraffiliation[García,MA] Unidad de Investigación, Hospital Universitario Virgen de las Nieves, Granada, Spain.[Aguilera,M] Unidad de Farmacogenética, Hospital Universitario Virgen de las Nieves, Granada, Spain.[García,MA; Carrasco,E; Alvarez,P; Prados,JC; Marchal,JA; Aránega,A] Instituto de Biopatología y Medicina Regenerativa (IBIMER), Universidad de Granada,Granada, Spain. [Rivas,C] Centro Nacional de Biotecnología, CSIC, Madrid,Spain. [Campos,JM] Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Granada, Spain.es
dc.contributor.funderThis work was supported in part by grants from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria projects n°. CP08/0063, PI07/0527 and PI10/02295). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
dc.date.accessioned2012-06-12T08:02:59Z
dc.date.available2012-06-12T08:02:59Z
dc.date.issued2011-08-24
dc.description.abstractThe chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR)as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNalpha treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner,inducing phosphorylation of the protein synthesis translation initiation factor eIF-2alpha and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNalpha combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug.es
dc.description.versionYeses
dc.identifier.citationGarcía MA, Carrasco E, Aguilera M, Alvarez P, Rivas C, Campos ,JM et al. The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in ap53-independent manner in colon and breast cancer cells. PLoS One. 2011;6(8):e23887es
dc.identifier.doi10.1371/journal.pone.0023887
dc.identifier.essn1932-6203
dc.identifier.pmid21887339
dc.identifier.urihttp://hdl.handle.net/10668/406
dc.journal.titlePLoS One
dc.language.isoen
dc.publisherPublic Library of Sciencees
dc.relation.publisherversionhttp://dx.plos.org/10.1371/journal.pone.0023887es
dc.rights.accessRightsopen access
dc.subjectAntimetabolitos Antineoplásicoses
dc.subjectNeoplasias de la Mamaes
dc.subjectLínea Celular Tumorales
dc.subjectNeoplasias del Colones
dc.subjectFemeninoes
dc.subjectFluorouraciles
dc.subjectHumanoses
dc.subjectFosforilaciónes
dc.subjecteIF-2 Quinasaes
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Antimetabolites::Antimetabolites, Antineoplastices
dc.subject.meshMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasmses
dc.subject.meshMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumores
dc.subject.meshMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms::Colonic Neoplasmses
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::Fluorouraciles
dc.subject.meshMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humanses
dc.subject.meshMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Phosphorylationes
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::eIF-2 Kinasees
dc.titleThe Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53-Independent Manner in Colon and Breast Cancer Cellses
dc.typeresearch article
dc.type.hasVersionVoR
dspace.entity.typePublication

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