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


Autoria(s): Garcia, María Angel; Carrasco, Esther; Aguilera, Margarita; Alvarez, Pablo; Rivas, Carmen; Campos, Joaquín Maria; Prados, José Carlos; Calleja, Miguel Angel; Esteban, Mariano; Marchal, Juan Antonio; Aranega, Antonia
Data(s)

12/06/2012

12/06/2012

24/08/2011

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