title: The chemotherapeutic drug 5-fluorouracil promotes PKR-mediated apoptosis in a p53-independent manner in colon and breast cancer cells.
abstract: 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.
authors: Unidad de Investigación, Hospital Universitario Virgen de las Nieves, Granada, Spain. mangelgarcia@ugr.es
authors: María Angel
authors: MA
authors: García
authors: Esther
authors: E
authors: Carrasco
authors: Margarita
authors: M
authors: Aguilera
authors: Pablo
authors: P
authors: Alvarez
authors: Carmen
authors: C
authors: Rivas
authors: Joaquin María
authors: JM
authors: Campos
authors: Jose Carlos
authors: JC
authors: Prados
authors: Miguel Angel
authors: MA
authors: Calleja
authors: Mariano
authors: M
authors: Esteban
authors: Juan Antonio
authors: JA
authors: Marchal
authors: Antonia
authors: A
authors: Aránega
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism* / Q000502:physiology
chemical_list: D000964:Antimetabolites, Antineoplastic; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019892:eIF-2 Kinase; D005472:Fluorouracil