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dc.contributor.authorWang, Weiguang
dc.contributor.authorCassidy, James
dc.contributor.authorO'Brien, Vincent
dc.contributor.authorRyan, Kevin
dc.contributor.authorCollie-Duguid, Elaina
dc.date.accessioned2008-06-04T13:00:35Z
dc.date.available2008-06-04T13:00:35Z
dc.date.issued2004
dc.identifier.citationCancer Research, 64 (22): 8167-76
dc.identifier.issn0008-5472
dc.identifier.pmid15548681
dc.identifier.doi10.1158/0008-5472.CAN-04-0970
dc.identifier.urihttp://hdl.handle.net/2436/29505
dc.description.abstractGene expression was analyzed in five pairs of 5-fluorouracil (5-FU) resistant and parental cancer cell lines on DNA microarrays. In unsupervised analysis, a prediction rule was built from the expression profiles of 29 genes, and 5-FU sensitivity class was predicted with 100% accuracy and high predictive strength. In supervised analysis of key 5-FU pathways, expression of 91 genes was associated with 5-FU sensitivity phenotype and segregated samples accordingly in hierarchical analysis. Key genes involved in 5-FU activation were significantly down-regulated (thymidine kinase, 2.9-fold; orotate phosphoribosyltransferase, 2.3-fold; uridine monophosphate kinase, 3.2-fold; pyrimidine nucleoside phosphorylase 3.6-fold) in resistant cells. Overexpression of thymidylate synthase and its adjacent gene, c-Yes, was detected in the resistant cell lines. The mRNA and protein overexpression of nuclear factor kappaB (NFkappaB) p65 and related antiapoptotic c-Flip gene was detected in resistant cells. The 5-FU-resistant cell lines also showed high NFkappaB DNA-binding activity. Cotransfection of NFkappaB p50 and p65 cDNA induced 5-FU resistance in MCF-7 cells. Both NFkappaB- and 5-FU-induced resistant cell lines manifested reduced expression of genes governing G(1)-S and S-phase transition. Expression of genes involved in DNA replication was also down-regulated in resistant cell lines. These findings were highly consistent with the slower growth rate, higher proportion of G(1), and lower proportion of S-phase cells in the resistant cell lines. This phenotype may protect resistant cells from cell death induced by incorporation of 5-FU into DNA chains, by allowing time to repair 5-FU-induced damage. Our findings may provide novel targets for tackling 5-FU resistance.
dc.language.isoen
dc.publisherAmerican Association for Cancer Research
dc.relation.urlhttp://cancerres.aacrjournals.org/cgi/content/full/64/22/8167
dc.subject.meshBase Sequence
dc.subject.meshCell Line, Tumor
dc.subject.meshDNA Primers
dc.subject.meshDown-Regulation
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshFlow Cytometry
dc.subject.meshFluorouracil
dc.subject.meshG1 Phase
dc.subject.meshGene Expression Profiling
dc.subject.meshHumans
dc.subject.meshOligonucleotide Array Sequence Analysis
dc.subject.meshPhenotype
dc.titleMechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells.
dc.typeArticle
dc.identifier.journalCancer Research
html.description.abstractGene expression was analyzed in five pairs of 5-fluorouracil (5-FU) resistant and parental cancer cell lines on DNA microarrays. In unsupervised analysis, a prediction rule was built from the expression profiles of 29 genes, and 5-FU sensitivity class was predicted with 100% accuracy and high predictive strength. In supervised analysis of key 5-FU pathways, expression of 91 genes was associated with 5-FU sensitivity phenotype and segregated samples accordingly in hierarchical analysis. Key genes involved in 5-FU activation were significantly down-regulated (thymidine kinase, 2.9-fold; orotate phosphoribosyltransferase, 2.3-fold; uridine monophosphate kinase, 3.2-fold; pyrimidine nucleoside phosphorylase 3.6-fold) in resistant cells. Overexpression of thymidylate synthase and its adjacent gene, c-Yes, was detected in the resistant cell lines. The mRNA and protein overexpression of nuclear factor kappaB (NFkappaB) p65 and related antiapoptotic c-Flip gene was detected in resistant cells. The 5-FU-resistant cell lines also showed high NFkappaB DNA-binding activity. Cotransfection of NFkappaB p50 and p65 cDNA induced 5-FU resistance in MCF-7 cells. Both NFkappaB- and 5-FU-induced resistant cell lines manifested reduced expression of genes governing G(1)-S and S-phase transition. Expression of genes involved in DNA replication was also down-regulated in resistant cell lines. These findings were highly consistent with the slower growth rate, higher proportion of G(1), and lower proportion of S-phase cells in the resistant cell lines. This phenotype may protect resistant cells from cell death induced by incorporation of 5-FU into DNA chains, by allowing time to repair 5-FU-induced damage. Our findings may provide novel targets for tackling 5-FU resistance.


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