ArticleMolecular cancer therapeutics2013
Uracil-DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed.
Article in Molecular cancer therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for Patients with Recurrent Glioblastoma in the Phase 2 Adult Brain Tumor Consortium Trial BERT.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Trial
- TTC33 forms a complex with WDR61 and PHF5A to recruit factors relevant to genomic integrity.Nature communications · 2026Article
- Silencing Uracil-DNA glycosylase inhibits colorectal cancer progression.Cancer cell international · 2026Article
- Article
- EXO1 as a therapeutic target for Fanconi Anaemia, ZRSR2 and BRCA1-A complex deficient cancers.Nature communications · 2025Article
- Cancer prognosis using base excision repair genes.Molecules and cells · 2025Review
- Cytotoxic mechanisms of pemetrexed and HDAC inhibition in non-small cell lung cancer cells involving ribonucleotides in DNA.Scientific reports · 2025Article
- Impact of DNA ligase inhibition on the nick sealing of polβ nucleotide insertion products at the downstream steps of base excision repair pathway.Mutagenesis · 2024Article
- Connecting dots between nucleotide biosynthesis and DNA lesion repair/bypass in cancer.Bioscience reports · 2024Review
- Detection of Uracil-Excising DNA Glycosylases in Cancer Cell Samples Using a Three-Dimensional DNAzyme Walker.ACS measurement science au · 2024Article
- Chemoresistance Mechanisms in Non-Small Cell Lung Cancer-Opportunities for Drug Repurposing.Applied biochemistry and biotechnology · 2024Review
- Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.Molecular cell · 2024Article
- Genetic Variants in Histone Modification Regions Predict Clinical Outcomes of Pemetrexed Chemotherapy in Lung Adenocarcinoma.Oncology · 2023Article
- Article
- A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme.Molecules (Basel, Switzerland) · 2021Article
- Anchored linear oligonucleotides: the effective tool for the real-time measurement of uracil DNA glycosylase activity.Open biology · 2021Article
- Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification.The Journal of clinical investigation · 2021Article
- An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation.Progress in biophysics and molecular biology · 2021Article
- Mechanisms of resistance to chemotherapy in non-small cell lung cancer.Archives of pharmacal research · 2021Review
- Base excision repair and its implications to cancer therapy.Essays in biochemistry · 2020Review
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3 authors.
Funding
Abstract
Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthase. The base excision repair (BER) enzyme uracil-DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG(-/-) human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human lung cancer cells. Higher levels of UNG are associated with pemetrexed resistance and are present in cell lines derived from pemetrexed-resistant histologic subtypes (small cell and squamous cell carcinoma). Acute pemetrexed exposure induces UNG protein and mRNA, consistent with upregulation of uracil-DNA repair machinery. Chronic exposure of H1299 adenocarcinoma cells to increasing pemetrexed concentrations established drug-resistant sublines. Significant induction of UNG protein confirmed upregulation of BER as a feature of acquired pemetrexed resistance. Cotreatment with the BER inhibitor methoxyamine overrides pemetrexed resistance in chronically exposed cells, underscoring the use of BER-directed therapeutics to offset acquired drug resistance. Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG upregulation is protective. In human lung cancer, UNG deficiency is associated with pemetrexed-induced retention of uracil in DNA that destabilizes DNA replication forks resulting in DNA double-strand breaks and cell death. Thus, in experimental models, UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value.
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