The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells
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AuthorGarcía Cháves, María Ángeles; Carrasco Pardo, Esther; Aguilera Gómez, Margarita; Álvarez, Pablo; Rivas, Carmen; Campos Rosa, Joaquín María; Prados Salazar, José Carlos; Calleja Hernández, Miguel Ángel; Esteban Rodríguez, Mariano; Marchal Corrales, Juan Antonio; Aránega Jiménez, Antonia
Public Library of Science (PLOS)
ApoptosisBreast cancerCancer treatmentColonColorectal cancerFlow cytometryPhosphorylationSW480 cells
García, M.A.; et al. The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells. Plos One, 6(8): e23887 (2011). [http://hdl.handle.net/10481/31134]
SponsorshipThis 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).
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/IFNα 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-2α 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/IFNα 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.