Dataset Information

FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance.

ABSTRACT: Fluorouracil (5-FU) is the first-line chemotherapeutic drug for cholangiocarcinoma (CCA), but its efficacy has been compromised by the development of resistance. Development of 5-FU resistance is associated with elevated expression of its cellular target, thymidylate synthase (TYMS). E2F1 transcription factor has previously been shown to modulate the expression of FOXM1 and TYMS. Immunohistochemical (IHC) analysis revealed a strong correlated upregulation of FOXM1 (78%) and TYMS (48%) expression at the protein levels in CCA tissues. In agreement, RT-qPCR and western blot analyses of four human CCA cell lines at the baseline level and in response to high doses of 5-FU revealed good correlations between FOXM1 and TYMS expression in the CCA cell lines tested, except for the highly 5-FU-resistant HuCCA cells. Consistently, siRNA-mediated knockdown of FOXM1 reduced the clonogenicity and TYMS expression in the relatively sensitive KKU-D131 but not in the highly resistant HuCCA cells. Interestingly, silencing of TYMS sensitized both KKU-D131 and HuCCA to 5-FU treatment, suggesting that resistance to very high levels of 5-FU is due to the inability of the genotoxic sensor FOXM1 to modulate TYMS expression. Consistently, ChIP analysis revealed that FOXM1 binds efficiently to the TYMS promoter and modulates TYMS expression at the promoter level upon 5-FU treatment in KKU-D131 but not in HuCCA cells. In addition, E2F1 expression did not correlate with either FOXM1 or TYMS expression and E2F1 depletion has no effects on the clonogenicity and TYMS expression in the CCA cells. In conclusion, our data show that FOXM1 regulates TYMS expression to modulate 5-FU resistance in CCA and that severe 5-FU resistance can be caused by the uncoupling of the regulation of TYMS by FOXM1. Our findings suggest that the FOXM1-TYMS axis can be a novel diagnostic, predictive and prognostic marker as well as a therapeutic target for CCA.

SUBMITTER: Intuyod K

PROVIDER: S-EPMC6290025 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance.

Intuyod Kitti K Saavedra-García Paula P Zona Stefania S Lai Chun-Fui CF Jiramongkol Yannasittha Y Vaeteewoottacharn Kulthida K Pairojkul Chawalit C Yao Shang S Yong Jay-Sze JS Trakansuebkul Sasanan S Waraasawapati Sakda S Luvira Vor V Wongkham Sopit S Pinlaor Somchai S Lam Eric W-F EW

Cell death & disease 20181211 12

Fluorouracil (5-FU) is the first-line chemotherapeutic drug for cholangiocarcinoma (CCA), but its efficacy has been compromised by the development of resistance. Development of 5-FU resistance is associated with elevated expression of its cellular target, thymidylate synthase (TYMS). E2F1 transcription factor has previously been shown to modulate the expression of FOXM1 and TYMS. Immunohistochemical (IHC) analysis revealed a strong correlated upregulation of FOXM1 (78%) and TYMS (48%) expression ...[more]

PMID: 30538221

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Project description:5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50-year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5'TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a predictive and prognostic factor.

Dataset Information

FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance.

Publications

FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance.

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