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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.
Highlights
The fluoropyrimidine 5-fluorouracil (5-FU) is widely used in the treatment of a range of cancers including colorectal cancer and breast tumors [1,2], but resistance to the drug remains a major clinical problem
While several reports have demonstrated that 5-FUinduced apoptosis is dependent on the tumour suppressor p53 protein, apoptosis can occur in mutant p53 cell lines by a mechanism still unknown [5,6,7].Since alterations in the mediators of 5-FU-induced apoptosis may account for chemo resistance, the identification of new targets involved in the 5-FU-induced apoptosis is of significant clinical interest
PKR protein is activated by 5-FU In order to explore if PKR is activated in response to 5-FU, we first analyzed PKR phosphorylation and that of its natural substrate eIF2a in several human colon and breast cancer cell lines. 5-FU treatment induced PKR phosphorylation in colon cancer SW-480 cells by 4 hours with a peak at 16 hours, whereas in breast cancer MCF7 cells, PKR activation was already detected 4 hours after treatment
Summary
The fluoropyrimidine 5-fluorouracil (5-FU) is widely used in the treatment of a range of cancers including colorectal cancer and breast tumors [1,2], but resistance to the drug remains a major clinical problem. 5-FU is converted into different active metabolites, including fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP). These metabolites have been implicated in both global RNA metabolism due to the incorporation of the ribonucleotide FUMP into RNA, and DNA metabolism due to thymidylate synthase (TS) inhibition or direct incorporation of FdUMP into DNA, leading to a wide range of biological effects which can act as triggers for apoptotic cell death [3,4]. While several reports have demonstrated that 5-FUinduced apoptosis is dependent on the tumour suppressor p53 protein, apoptosis can occur in mutant p53 cell lines by a mechanism still unknown [5,6,7].Since alterations in the mediators of 5-FU-induced apoptosis may account for chemo resistance, the identification of new targets involved in the 5-FU-induced apoptosis is of significant clinical interest
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