ArticleAnnals of translational medicine2021
Repressing PDCD4 activates JNK/ABCG2 pathway to induce chemoresistance to fluorouracil in colorectal cancer cells.
Article in Annals of translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 16 citations in OpenAlex.
- Chitosan/β-cyclodextrin nanocarriers enhance 5-fluorouracil efficacy against colorectal cancer via pH-responsive release and apoptosis modulation.Scientific reports · 2026Article
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- Biological Performance and Molecular Mechanisms of Mesyl MicroRNA-Targeted Oligonucleotides in Colorectal Cancer Cells.International journal of molecular sciences · 2025Article
- Role of microRNA-761 in modulating laryngeal cancer cell proliferation, metastasis, and apoptosis: regulation of PDCD4 as a key mechanism.Molecular biology reports · 2025Article
- Oleocanthal as a Multifunctional Anti-Cancer Agent: Mechanistic Insights, Advanced Delivery Strategies, and Synergies for Precision Oncology.International journal of molecular sciences · 2025Review
- DMGAT: predicting ncRNA-drug resistance associations based on diffusion map and heterogeneous graph attention network.Briefings in bioinformatics · 2025Article
- The Impact of Pdcd4, a Translation Inhibitor, on Drug Resistance.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Monosaccharide Composition and In Vitro Activity to HCT-116 Cells of Purslane Polysaccharides after a Covalent Chemical Selenylation.Foods (Basel, Switzerland) · 2022Article
- Multidrug efflux transporter ABCG2: expression and regulation.Cellular and molecular life sciences : CMLS · 2021Review
- Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundColorectal cancer (CRC) is the third major cause of cancer-related death worldwide, and fluorouracil (5-FU) is widely used in the treatment of CRC. However, acquired resistance to 5-FU has become an obstacle in the effective treatment of CRC. Adenosine triphosphate (ATP)-binding cassette sub-family G member 2 (ABCG2) has been found highly expressed in CRC patients with poor responsiveness to folinic acid/5-FU/irinotecan. However, the mechanisms of 5-FU resistance regulated by ABCG2 in CRC cells remain to be comprehensively understood. We aimed to explore the upstream mechanisms of ABCG2 involved in the regulation of chemoresistance in CRC cells.
methodsWe investigated the potential mechanisms of 5-FU resistance in HCT116, RKO, RKO microRNA-21 (miR-21) knockout, and acquired 5-FU-resistant HCT116 (HCT116/FUR) cells. The biochemical and biological analyses were conducted using semiquantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, transfections, and rescue experiments, along with cell proliferation, viability, and colony formation assays. In order to investigate the efficacy of inhibiting the c-Jun NH2 terminal kinase (JNK) pathway to overcome 5-FU resistance, HCT116 and 5-FU-resistant HCT116 cells were inoculated into BALB/c-nu/nu mice to establish the cell-derived xenograft model.
resultsThe results showed that ABCG2 expression in HCT116/FUR cells was higher compared to HCT116 cells. Overexpression of ABCG2 decreased sensitivity to 5-FU in HCT116 cells, but knockdown of ABCG2 decreased the survival rate in HCT116/FUR cells. Additionally, repressing programmed cell death 4 (PDCD4) activated the JNK pathway in HCT116/FUR cells. Overexpression of PDCD4 inhibited phosphorylation of c-Jun and ABCG2 expression, and recovered sensitivity to 5-FU in HCT116/FUR cells. Moreover, treatment with the JNK pathway inhibitor SP600125 downregulated ABCG2 expression and rescued sensitivity to 5-FU in HCT116/FUR cells. We also found that miR-21 expression in HCT116/FUR cells was higher compared to HCT116 cells. Finally, 5-FU treatment in combination with SP600125 significantly decreased tumorigenicity compared to other treatments
conclusionsOur results demonstrated that 5-FU treatment upregulated miR-21, which directly repressed PDCD4, and subsequently activated the JNK pathway, leading to the upregulation of ABCG2 in CRC cells. Inhibition of the JNK pathway overcame acquired 5-FU resistance both
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