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 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.