P2X7 receptor contributes to DNA damage repair and acquisition of malignant phenotypes in irradiated human glioblastoma cells

Radiation therapy for cancer takes advantage of the higher sensitivity of tumor cells to radiation compared to normal tissue, but some cancers, such as glioblastoma (GBM) and malignant melanoma, acquire radiation resistance (radioresistance), rendering treatment ineffective. Radioresistance is chara...

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Vydáno v:Biochimica et biophysica acta. General subjects Ročník 1869; číslo 12; s. 130873
Hlavní autoři: Seki, Hiromu, Kitabatake, Kazuki, Uchiumi, Fumiaki, Tanuma, Sei-ichi, Tsukimoto, Mitsutoshi
Médium: Journal Article
Jazyk:angličtina
Vydáno: Netherlands Elsevier B.V 01.12.2025
Témata:
Adenosine Triphosphate - metabolism
Brain Neoplasms - genetics
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
Cell Line, Tumor
Cell migration
Cell Movement - drug effects
Cell Movement - radiation effects
DNA Damage - radiation effects
DNA repair
DNA Repair - radiation effects
Gamma Rays
Glioblastoma
Glioblastoma - genetics
Glioblastoma - metabolism
Glioblastoma - pathology
Glioblastoma - radiotherapy
HMGB1
HMGB1 Protein - metabolism
Humans
P2X7 receptor
Phenotype
Purinergic P2X Receptor Antagonists - pharmacology
Radiation
Radiation Tolerance
Receptors, Purinergic P2X7 - genetics
Receptors, Purinergic P2X7 - metabolism
HMGB1
DNA repair
P2X7 receptor
Cell migration
Glioblastoma
Radiation
ISSN:0304-4165, 1872-8006, 1872-8006
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Shrnutí:Radiation therapy for cancer takes advantage of the higher sensitivity of tumor cells to radiation compared to normal tissue, but some cancers, such as glioblastoma (GBM) and malignant melanoma, acquire radiation resistance (radioresistance), rendering treatment ineffective. Radioresistance is characterized by strong activation of DNA repair mechanisms in response DNA damage induced by radiation, together with possession of malignant property such as enhanced invasiveness and metastasis, though the molecular mechanisms involved remain to be fully established. Here, we show that P2X7 receptor-specific inhibitors suppress the γ-irradiation-induced DNA damage response (DDR) and enhance cell death of A172 GBM cells. In contrast, ATP, a P2X7 receptor ligand, promotes the DDR and suppresses cell death. Irradiation immediately induced ATP release from cells, and P2X7 receptor inhibitor suppressed the release of ATP. Furthermore, P2X7 receptor inhibitors suppress the release of high mobility group box 1 (HMGB1), which is known to promote cancer cell migration. Inhibitors of the receptor for advanced glycation end products (RAGE) also suppress ATP-induced cell motility, indicating that the P2X7-HMGB1-RAGE pathway contributes to radiation-induced malignant transformation. These data indicate firstly that the P2X7 receptor promotes the γ-irradiation-induced DDR, leading to increased resistance of GBM cells to γ-radiation-induced death, and secondly that the P2X7 receptor and extracellular ATP may be involved in the γ-irradiation-induced acquisition of malignant property such as cytoskeletal changes and enhanced motility in GBM cells. [Display omitted] •γ-Radiation induces DNA repair and promotes migration of A172 glioblastoma cells.•P2X7 receptor inhibitors suppress DNA repair and cell migration after irradiation.•The P2X7 ligand ATP enhances DNA repair and cell migration of A172 cells.•P2X7 receptor promotes cell migration through HMGB1 - RAGE signaling.•P2X7 receptor is a candidate target to increase the efficacy of radiotherapy.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0304-4165
1872-8006
1872-8006
DOI:10.1016/j.bbagen.2025.130873