Analysis of uracil DNA glycosylase in human colorectal cancer

Dusseau, Caroline; Murray, Graeme I.; Keenan, Ron A.; O'Kelly, Terry; Krokan, Hans E.; McLeod, Howard L.

doi:10.3892/ijo.18.2.393

Cited by 13 publications

(14 citation statements)

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“…In contrast to current understanding of dUTPase, relatively little information exists on the role of UDG in this cytotoxic process (36,37). Data presented here indicate that both the nuclear and the mitochondrial isoforms of UDG are modulated by FdUrd treatment in certain cell lines but not in others.…”

Section: Discussioncontrasting

confidence: 41%

Fluorodeoxyuridine Modulates Cellular Expression of the DNA Base Excision Repair Enzyme Uracil-DNA Glycosylase

Fischer¹,

Muller-Weeks²,

Caradonna³

2006

Cancer Research

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The thymidylate synthase inhibitor 5-fluorouracil (5-FU) continues to play a pivotal role in the treatment of cancer. A downstream event of thymidylate synthase inhibition involves the induction of a self-defeating base excision repair process. With the depletion of TTP pools, there is also an increase in dUMP. Metabolism of dUMP to the triphosphate dUTP results in elevated pools of this atypical precursor for DNA synthesis. Under these conditions, there is a destructive cycle of dUMP incorporation into DNA, removal of uracil by the base excision repair enzyme uracil-DNA glycosylase (UDG), and reincorporation of dUMP during the synthesis phase of DNA repair. The end point is DNA strand breaks and loss of DNA integrity, which contributes to cell death. Evidence presented here indicates that both the nuclear and the mitochondrial isoforms of UDG are modulated by FdUrd (and 5-FU) treatment in certain cell lines but not in others. Modulation occurs at the transcriptional and post-translational levels. Under normal conditions, nUDG protein appears in G 1 and is degraded during the S to G 2 phase transition. The present study provides evidence that, in certain cell lines, FdUrd mediates an atypical turnover of nUDG. Additional data indicate that, for cell lines that do not down-regulate nUDG, small interfering RNA-mediated knockdown of nUDG significantly increases resistance to the cytotoxic effects of FdUrd.Results from these studies show that nUDG is an additional determinant in FdUrd-mediated cytotoxicity and bolster the notion that the self-defeating base excision repair pathway, instigated by elevated dUTP (FdUTP) pools, contributes to the cytotoxic consequences of 5-FU chemotherapy. (Cancer Res 2006; 66(17): 8829-37)

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Section: Discussioncontrasting

confidence: 41%

Fluorodeoxyuridine Modulates Cellular Expression of the DNA Base Excision Repair Enzyme Uracil-DNA Glycosylase

Fischer¹,

Muller-Weeks²,

Caradonna³

2006

Cancer Research

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“…UNG is the gene encoding uracil-DNA glycosylase, a base excision repair protein involved in uracil excision from DNA. Both these enzymes are reported to mediate response to the antimetabolite class of chemotherapeutic agents including inhibitors of TS such as 5-fluorouracil [55,56]. A number of other studies have confirmed that downregulation of TS mRNA and protein is a common event in response to HDACi treatment [14,25,57].…”

Section: Discussionmentioning

confidence: 99%

DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines

et al. 2009

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BackgroundDespite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.MethodsHCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity® Pathway Analysis.ResultsTreatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.ConclusionThis study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.

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“…Large increases in UNG1 expression in 5-FU-resistant cells [40] indicate that it may be a major contributor of resistance to 5-FU in CCA cell lines. Our results show TP73 downregulation in all four resistant cell lines although the fold of expression was not linearly related to their basal IC 50 values.…”

Section: Discussionmentioning

confidence: 99%

Characterization of 5-Fluorouracil-Resistant Cholangiocarcinoma Cell Lines

et al. 2008

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Background: Although 5-fluorouracil (5-FU) is the drug of choice for the palliative treatment of cholangiocarcinoma (CCA), resistance to the drug is a therapeutic obstacle. The aim of this study was to explore the mechanisms underlying 5-FU resistance of CCA using cell lines derived from CCA associated with liver fluke infection. Methods: A stepwise exposure was used for inducing 5-FU-resistant CCA cell lines, and the expression of nine genes associated with 5-FU resistance was analyzed using real-time (RT)-PCR. Results: Altered expression of several genes involved in 5-FU resistance in CCA cell lines was observed. The expression levels of almost all target genes investigated including TP, DPD, ENT1, UNG1, TOP2A, BIRC5, TP73 and DeltaNp73 appeared to be significantly altered in these resistant strains. The expression of the TS gene tended to be increased but the fold change was not significantly different from their parental cell lines. UNG1 (a DNA repairing enzyme) and BIRC5 (an apoptotic inhibitor) expressions were increased whereas TP73 (a proapoptotic factor) expression levels decreased concomitantly. Conclusion: Our study showed that increases in UNG1 and BIRC5 expression and concomitant decreases in TP73 expression may be associated with development of acquired 5-FU resistance in CCA lines and their phenotypes.

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Analysis of uracil DNA glycosylase in human colorectal cancer

Cited by 13 publications

References 0 publications

Fluorodeoxyuridine Modulates Cellular Expression of the DNA Base Excision Repair Enzyme Uracil-DNA Glycosylase

Fluorodeoxyuridine Modulates Cellular Expression of the DNA Base Excision Repair Enzyme Uracil-DNA Glycosylase

DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines

Characterization of 5-Fluorouracil-Resistant Cholangiocarcinoma Cell Lines

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