The chemotherapeutic drug 5-fluorouracil promotes PKR-mediated apoptosis in a p53-independent manner in colon and breast cancer 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...
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| Veröffentlicht in: | PloS one 2011-08, Vol.6 (8), p.e23887 |
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| creator | García, María Angel Carrasco, Esther Aguilera, Margarita Alvarez, Pablo Rivas, Carmen Campos, Joaquin María Prados, Jose Carlos Calleja, Miguel Angel Esteban, Mariano Marchal, Juan Antonio Aránega, Antonia |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0023887 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0023887</identifier><identifier>PMID: 21887339</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>5-Fluorouracil ; Analysis ; Anticancer properties ; Antimetabolites, Antineoplastic - pharmacology ; Antitumor activity ; Apoptosis ; Biology ; Biotechnology ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - pathology ; Cancer ; Cell death ; Cell Line, Tumor ; Chemotherapy ; Colon ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - pathology ; Cytotoxicity ; Drug resistance ; Drug therapy ; eIF-2 kinase ; eIF-2 Kinase - metabolism ; eIF-2 Kinase - physiology ; Female ; Fluorouracil ; Fluorouracil - pharmacology ; Humans ; Kinases ; Medicine ; Metabolites ; p53 Protein ; Phosphorylation ; Protein biosynthesis ; Protein kinase ; Protein kinases ; Protein synthesis ; Ribonucleic acid ; RNA ; Target recognition ; Translation (Genetics) ; Tumor cell lines ; Tumor proteins ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>PloS one, 2011-08, Vol.6 (8), p.e23887</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Garcia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>5-Fluorouracil</subject><subject>Analysis</subject><subject>Anticancer properties</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Biotechnology</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Colon</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - pathology</subject><subject>Cytotoxicity</subject><subject>Drug resistance</subject><subject>Drug therapy</subject><subject>eIF-2 kinase</subject><subject>eIF-2 Kinase - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21887339</pmid><doi>10.1371/journal.pone.0023887</doi><tpages>e23887</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-08, Vol.6 (8), p.e23887 |
| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 5-Fluorouracil Analysis Anticancer properties Antimetabolites, Antineoplastic - pharmacology Antitumor activity Apoptosis Biology Biotechnology Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - pathology Cancer Cell death Cell Line, Tumor Chemotherapy Colon Colon cancer Colonic Neoplasms - drug therapy Colonic Neoplasms - pathology Cytotoxicity Drug resistance Drug therapy eIF-2 kinase eIF-2 Kinase - metabolism eIF-2 Kinase - physiology Female Fluorouracil Fluorouracil - pharmacology Humans Kinases Medicine Metabolites p53 Protein Phosphorylation Protein biosynthesis Protein kinase Protein kinases Protein synthesis Ribonucleic acid RNA Target recognition Translation (Genetics) Tumor cell lines Tumor proteins Tumor Suppressor Protein p53 - metabolism |
| title | The chemotherapeutic drug 5-fluorouracil promotes PKR-mediated apoptosis in a p53-independent manner in colon and breast cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-30T22%3A16%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20chemotherapeutic%20drug%205-fluorouracil%20promotes%20PKR-mediated%20apoptosis%20in%20a%20p53-independent%20manner%20in%20colon%20and%20breast%20cancer%20cells&rft.jtitle=PloS%20one&rft.au=Garc%C3%ADa,%20Mar%C3%ADa%20Angel&rft.date=2011-08-24&rft.volume=6&rft.issue=8&rft.spage=e23887&rft.pages=e23887-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0023887&rft_dat=%3Cgale_plos_%3EA476881788%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1308408499&rft_id=info:pmid/21887339&rft_galeid=A476881788&rft_doaj_id=oai_doaj_org_article_cf60efa20b314181a01b521f2840ed51&rfr_iscdi=true |