Glioblastoma (GBM) is the most common primary brain tumor and is highly aggressive with a median survival of 15 months. We have previously shown that residual cells of GBM form multinucleated giant cells (MNGCs) showing a senescent phenotype, but eventually escape from therapy induced senescence (TIS), resulting in GBM recurrence. Here we demonstrate the role of PARP-1 in TIS and its recovery. We show that genetic and pharmacological inhibition of PARP-1 has an anti-proliferative effect on GBM cell lines and primary cultures derived from patient samples. Furthermore, the PARP-1 inhibitor olaparib, in combination with radiation increased MNGCs formation and senescence as assessed by β-galactosidase activity, and macroH2A1 levels in residual cells. Additionally, we found that reduced PARP-1 activity and not protein levels in residual cells was crucial for MNGCs formation and their maintenance in the senescent state. PARP-1 activity was restored to higher levels in recurrent cells that escaped from TIS. Importantly, olaparib + radiation treatment significantly delayed recurrence in vitro as well in vivo in orthotopic GBM mouse models with a significant increase in overall survival of mice. Overall, this study demonstrates that sustained inhibition of PARP-1 activity during radiation treatment significantly delays GBM recurrence.

胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，具有很高的侵袭性，中位生存期为15个月。先前我们已经表明，GBM的残留细胞形成多核巨细胞（MNGC），表现出衰老的表型，但最终逃脱了治疗诱导的衰老（TIS），导致GBM复发。在这里，我们演示了PARP-1在TIS中的作用及其恢复。我们表明，PARP-1的遗传和药理抑制作用对GBM细胞系和源自患者样品的原代培养具有抗增殖作用。此外，PARP-1抑制剂olaparib与放射线结合可增加MNGC的形成和衰老，这可通过β-半乳糖苷酶活性和残余细胞中的macroH2A1水平进行评估。另外，我们发现减少的PARP-1活性而不是残留细胞中的蛋白质水平对于MNGC的形成及其在衰老状态的维持至关重要。从TIS逃脱的复发细胞中PARP-1活性恢复到较高水平。重要的是，奥拉帕尼+放射治疗显着延迟了复发原位GBM小鼠模型的体外和体内实验，小鼠的总体存活率显着提高。总体而言，这项研究表明放射治疗期间对PARP-1活性的持续抑制显着延迟了GBM的复发。