The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53-Independent Manner in Colon and Breast Cancer Cells
Data(s) |
12/06/2012
12/06/2012
24/08/2011
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Resumo |
The 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. This 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 |
Identificador |
García 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):e23887 1932-6203 (Online) http://hdl.handle.net/10668/406 21887339 10.1371/journal.pone.0023887 |
Idioma(s) |
en |
Publicador |
Public Library of Science |
Relação |
PLoS One http://dx.plos.org/10.1371/journal.pone.0023887 |
Direitos |
Acceso abierto |
Palavras-Chave | #Antimetabolitos Antineoplásicos #Neoplasias de la Mama #Línea Celular Tumoral #Neoplasias del Colon #Femenino #Fluorouracil #Humanos #Fosforilación #eIF-2 Quinasa #Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Antimetabolites::Antimetabolites, Antineoplastic #Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms #Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor #Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms::Colonic Neoplasms #Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::Fluorouracil #Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans #Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Phosphorylation #Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::eIF-2 Kinase |
Tipo |
info:eu-repo/semantics/article info:eu-repo/semantics/published Artículo |