Sustained inhibition of PARP-1 activity delays glioblastoma recurrence by enhancing radiation-induced senescence
Sustained inhibition of PARP-1 activity delays glioblastoma recurrence by enhancing radiation-induced senescence
复制标题
DOI：
10.1016/j.canlet.2020.06.023
复制
发表时间：
2020-10-10
期刊：
影响因子：
9.7
通讯作者：
Dutt, Shilpee
中科院分区：
文献类型：
--
作者：
Ghorai, Atanu;Mahaddalkar, Tejashree;Dutt, Shilpee
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，具有高度侵袭性，中位生存期为15个月。我们先前已经表明，GBM的残余细胞形成显示衰老表型的多核巨细胞（MNGC），但最终逃避治疗诱导的衰老（TIS），导致GBM复发。在这里，我们展示了PARP-1在TIS及其恢复中的作用。我们表明，PARP-1的遗传和药理学抑制对来自患者样本的GBM细胞系和原代培养物具有抗增殖作用。此外，PARP-1抑制剂奥拉帕尼与辐射结合增加了MNGC的形成和衰老，如通过β-半乳糖苷酶活性和残留细胞中的macroH 2A 1水平所评估的。此外，我们发现残留细胞中PARP-1活性的降低而不是蛋白水平的降低对于MNGC的形成及其在衰老状态下的维持至关重要。在从TIS逃逸的复发细胞中，PARP-1活性恢复到较高水平。重要的是，奥拉帕尼+放射治疗在原位GBM小鼠模型中显著延迟了体外和体内复发，小鼠的总生存期显著增加。总体而言，本研究表明，放射治疗期间持续抑制PARP-1活性可显著延迟GBM复发。
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 beta-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.