ArticleOncotarget2015
Acquired resistance to 5-fluorouracil via HSP90/Src-mediated increase in thymidylate synthase expression in colon cancer.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 57 citations in OpenAlex.
- ER-Localized DeadenylaseExploration (Beijing, China) · 2026Article
- Multi-Omics Analysis of TYMS as a Prognostic Biomarker and Therapeutic Target for Lung Adenocarcinoma.Cancer medicine · 2026Article
- Methionine restriction for cancer therapy: From preclinical studies to clinical trials.Cancer pathogenesis and therapy · 2026Review
- Computational Elucidation of Hub Genes and Pathways Correlated with the Development of 5-Fluorouracil Resistance in HCT 116 Colorectal Carcinoma Cell Line.Biochemical genetics · 2026Article
- A Holistic Review of Oncological Drug Targets and Trajectories of Resistance in Cancer Therapy.Oncology research · 2026Review
- Mutation and Microsatellite Instability (MSI) Affect the Differential Gene Expression of Folic Acid and 5-Flourouracil Metabolism-Related Genes in Colorectal Carcinoma.Current oncology (Toronto, Ont.) · 2025Article
- Comprehensive review of the resistance mechanisms of colorectal cancer classified by therapy type.Frontiers in immunology · 2025Review
- Farrerol inhibits proliferation and migration of colorectal cancer via the VEGF signaling pathway: evidence from network pharmacology, molecular docking, molecular dynamics simulation, andFrontiers in pharmacology · 2025Article
- Article
- Role of c-Src in Carcinogenesis and Drug Resistance.Cancers · 2023Review
- Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-target effects.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Article
- Antitumor Effect of Cycloastragenol in Colon Cancer Cells via p53 Activation.International journal of molecular sciences · 2022Article
- Learn from antibody-drug conjugates: consideration in the future construction of peptide-drug conjugates for cancer therapy.Experimental hematology & oncology · 2022Review
- An open-label, crossover study to compare different formulations and evaluate effect of food on pharmacokinetics of pimitespib in patients with advanced solid tumors.Investigational new drugs · 2022Article
- Downregulation of KRAB zinc finger proteins in 5-fluorouracil resistant colorectal cancer cells.BMC cancer · 2022Article
- Review
- Baseline serum uric acid level is associated with progression-free survival, disease control rate, and safety in postoperative patients with colorectal cancer treated by FOLFOX, FOLFIRI, or XELOX.Frontiers in oncology · 2022Article
- The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer.Molecular oncology · 2021Article
- Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation.Cell death and differentiation · 2021Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
5-fluorouracil (5-FU), one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU-sensitive HCT116 colon cancer cells morphologic, molecular, and behavioral characteristic of the epithelial-mesenchymal transition (EMT), contributing to emergence of acquired resistance to 5-FU. HCT116/R, a HCT116 colon cancer cell subline carrying acquired resistance to 5-FU, showed increased expression and activation of HSP90's client proteins and transcriptional up-regulation of TYMS. Forced overexpression of HSP90 or constitutive active Src in HCT116 cells increased TYMS expression. Conversely, pharmacological blockade of HSP90 or Src in HCT116/R cells effectively suppressed the changes involved in 5-FU resistance in vitro and xenograft tumor growth, hematogenous spread, and metastatic tumor development in vivo. This study suggests a novel function of HSP90-Src pathway in regulation of TYMS expression and acquisition of 5-FU resistance. Thus, therapeutics targeting this pathway may be an effective clinical strategy to overcome 5-FU resistance in colon cancer.
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