The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells García Chaves, María Ángel 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 Apoptosis Breast cancer Cancer treatment Colon Colorectal cancer Flow cytometry Phosphorylation SW480 cells 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. 2014-03-26T13:35:31Z 2014-03-26T13:35:31Z 2011 info:eu-repo/semantics/article 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] 1932-6203 doi: 10.1371/journal.pone.0023887 http://hdl.handle.net/10481/31134 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ info:eu-repo/semantics/openAccess Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Public Library of Science (PLOS)