ArticleBMC cancer2019
Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in some brain tumour cells.
Article in BMC cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Radiation therapy increases long-term gonadotropin deficiency, hypothalamic-pituitary dysfunction, and brainstem necrosis in pediatric patients with brain tumor.Radiation oncology journal · 2026Article
- Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma.Frontiers in cell and developmental biology · 2022Review
- Hypoxia Enhances Glioma Resistance to Sulfasalazine-Induced Ferroptosis by Upregulating SLC7A11 via PI3K/AKT/HIF-1Oxidative medicine and cellular longevity · 2022Article
- Hypoxia and its therapeutic possibilities in paediatric cancers.British journal of cancer · 2021Review
- Specific Protein 1 and p53 Interplay Modulates the Expression of the KCTD-Containing Cullin3 Adaptor Suppressor of Hedgehog 2.Frontiers in cell and developmental biology · 2021Article
- Article
- Hypoxia in Solid Tumors: How Low Oxygenation Impacts the "Six Rs" of Radiotherapy.Frontiers in endocrinology · 2021Review
- Inside the hypoxic tumour: reprogramming of the DDR and radioresistance.Cell death discovery · 2020Review
- MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment.Molecular cancer · 2019Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundSolid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. We aimed to elucidate the impact of hypoxia on the sensitivity of MB cells to chemo- and radiotherapy.
methodsWe used two MB cell line (D283-MED and MEB-Med8A) and a widely used glioblastoma cell line (U87MG) for comparison. We applied a range of molecular and cellular techniques to measure cell survival, cell cycle progression, protein expression and DNA damage combined with a transcriptomic micro-array approach in D283-MED cells, for global gene expression analysis in acute and chronic hypoxic conditions.
resultsIn D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to chemotherapy and X-ray irradiation. This acquired resistance upon chronic hypoxia was present but less pronounced in MEB-Med8A cells. Using transcriptomic analysis in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway.
conclusionTogether our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB in D283-MED cells, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols.
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