Influence of thymidylate synthase expression on survival in patients with colorectal cancer

Gajjar, Kinjal; Kobawala, Toral P; Trivedi, Trupti; Vora, Hemangini H.; Ghosh, Nandita

doi:10.4103/ijamr.ijamr_32_17

Cited by 2 publications

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“…Moreover, its correlation with the mucinous type of CRC tumours was presented in Glasgow et al 22 In this study, FP therapy caused no changes in the methylation of TS gene promoter, while a significant induction of TS expression after therapy was observed. An association between high TS expression and resistance to 5-FU therapy was demonstrated in Gajjar et al 9 The overexpression of TS was linked to lack of DNA repair through DNA hypomethylation, and high microsatellite instability. 23 The inactivation of TS gene with FP analogues, such as 5-FU resulted in depletion of a Is a significant difference when CRC patients after 3 and 6 months of FP therapy were compared with their baseline level, P value ⩽.05.…”

Section: Discussionmentioning

confidence: 90%

“…8 TS, the rate-limiting enzyme of DNA synthesis, is a valuable target for many antimetabolite drugs such as 5-fluorouracil (5-FU), and its level of expression is proportional with the response of CRC patients to 5-FU therapy. 9 TS expression was found to be epigenetically regulated by microRNA-215. 10 This microRNA controls the sensitivity of colon cancer cells to TS inhibitor drugs through increasing the G2/M cell cycle check point and reducing the proliferation of cells.…”

Section: Epigenetics Insightsmentioning

confidence: 99%

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The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer

et al. 2021

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Aims: This study investigated the impact of promoter methylation of flouropyrimidine (FP) metabolizing and cyclooxygenase 2 (COX2) genes on their mRNA expression and on the clinical outcome of colorectal cancer (CRC) patients. Methods: Methylation specific-PCR and real time-PCR of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and COX2 were performed at baseline and after 3 and 6 months of FP therapy. Pairwise comparisons were conducted between the subgroups of CRC patients. The event free survival (EFS) and the hazard of progression were estimated by univariate and multivariate analyses. Results: At baseline CRC patients, both TS and TP were overexpressed, in spite of the unmethylation of TS and the full methylation of TP genes. Significant downexpression of DPD and COX2 were associated their promoter’s methylation. At the end of FP therapy, TS, DPD and COX2 were overexpressed by 7.52, 2.88 and 3.45 folds, respectively, while TP was downexpressed by 0.54 fold. However, no change was observed in the methylation status of genes with FP therapy. Pairwise comparisons revealed significant difference in the expression and the methylation status of genes according to the clinicopathological characters of CRC patients either at baseline or after FP therapy. The overexpression of DPD and COX2 genes were indicators for a poor EFS of CRC patients. Also, the high level of COX2 expression was found to be significantly correlated with the hazard of progression (HR = 1.73, 95% CI = 1.02-3.03). Conclusion: The promoter methylation of FP metabolizing and COX2 genes has significant impact on the expression and the treatment outcome of CRC patients.

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Section: Discussionmentioning

confidence: 90%

Section: Epigenetics Insightsmentioning

confidence: 99%

The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer

et al. 2021

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Thymidylate synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer

et al. 2021

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Alteration of O-GlcNAcylation, a dynamic post-translational modification, is associated with tumorigenesis and tumor progression. Its role in chemotherapy response is poorly investigated. Standard treatment for colorectal cancer (CRC), 5-fluorouracil (5-FU), mainly targets Thymidylate Synthase (TS). TS O-GlcNAcylation was reported but not investigated yet. We hypothesize that O-GlcNAcylation interferes with 5-FU CRC sensitivity by regulating TS. In vivo, we observed that combined 5-FU with Thiamet-G (O-GlcNAcase (OGA) inhibitor) treatment had a synergistic inhibitory effect on grade and tumor progression. 5-FU decreased O-GlcNAcylation and, reciprocally, elevation of O-GlcNAcylation was associated with TS increase. In vitro in non-cancerous and cancerous colon cells, we showed that 5-FU impacts O-GlcNAcylation by decreasing O-GlcNAc Transferase (OGT) expression both at mRNA and protein levels. Reciprocally, OGT knockdown decreased 5-FU-induced cancer cell apoptosis by reducing TS protein level and activity. Mass spectrometry, mutagenesis and structural studies mapped O-GlcNAcylated sites on T251 and T306 residues and deciphered their role in TS proteasomal degradation. We reveal a crosstalk between O-GlcNAcylation and 5-FU metabolism in vitro and in vivo that converges to 5-FU CRC sensitization by stabilizing TS. Overall, our data propose that combining 5-FU-based chemotherapy with Thiamet-G could be a new way to enhance CRC response to 5-FU.

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Influence of thymidylate synthase expression on survival in patients with colorectal cancer

Cited by 2 publications

References 0 publications

The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer

The Clinical Significance of Promoter Methylation of Fluoropyrimidine Metabolizing and Cyclooxygenase Genes in Colorectal Cancer

Thymidylate synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer

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