ArticleOncoTargets and therapy2019
Induction Of XLF And 53BP1 Expression Is Associated With Temozolomide Resistance In Glioblastoma Cells.
Article in OncoTargets and therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 18 citations in OpenAlex.
- GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress.Cancer discovery · 2024Article
- Discovery of a 53BP1 Small Molecule Antagonist Using a Focused DNA-Encoded Library Screen.Journal of medicinal chemistry · 2023Article
- An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering.Nature communications · 2023Article
- Multifaceted regulation and functions of 53BP1 in NHEJ‑mediated DSB repair (Review).International journal of molecular medicine · 2022Review
- The component of the mJournal of experimental & clinical cancer research : CR · 2021Article
- Elevated XRCC5 expression level can promote temozolomide resistance and predict poor prognosis in glioblastoma.Oncology letters · 2021Article
- Inhibition of SETMAR-H3K36me2-NHEJ repair axis in residual disease cells prevents glioblastoma recurrence.Neuro-oncology · 2020Article
Corrections and comments
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionGlioblastoma (GBM) is the most commonly diagnosed primary brain tumor in adults. The 14.6 months median survival period of GBM patients is still palliative due to resistance to the first-line chemotherapeutic agent temozolomide (TMZ).
methodsThe cell growth inhibition effect was assessed using the SRB assay. The mRNA expression levels were examined using RT-qPCR. The protein expression levels were determined using Western blot analysis. The DNA repair by non-homologous end-joining (NHEJ) was quantified using NHEJ reporter assay. The TMZ-induced apoptosis was detected by the Caspase 3/7 activity kit. The DNA binding activity in cells was determined using chromatin fractionation assay. The 53BP1 inhibitor was identified using virtual screening followed by Western blot analysis. The synergy between TMZ and 53BP1 inhibitor in vivo was analyzed using a xenograft mouse model.
resultsWe found that non-homologous end joining (NHEJ), which is one of the major DNA double-strand break repair pathways, participates in acquired TMZ-resistance in GBM. Canonical NHEJ key factors, XLF and 53BP1, are upregulated in TMZ-resistant GBM cells. Depletion of XLF or 53BP1 in TMZ-resistant cells significantly improve the potency of TMZ against GBM cell growth. Importantly, we identified a small molecule HSU2018 to inhibit 53BP1 at nanomolar concentration. The combination of HSU2018 and TMZ generates excellent synergy for cell growth inhibition in TMZ-resistant GBM cells and xenograft.
conclusionOur data suggest that NHEJ is a novel mechanism contributing to TMZ-resistance, and its key factors may serve as potential targets for improving chemotherapy in TMZ-resistant GBM.
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