聚ADP核糖聚合酶
癌症研究
衰老
奥拉帕尼
克隆形成试验
体内
放射治疗
辐射灵敏度
PARP抑制剂
生物
医学
内科学
细胞生物学
遗传学
聚合酶
基因
辐照
物理
核物理学
作者
Atanu Ghorai,Tejashree Mahaddalkar,Rahul Thorat,Shilpee Dutt
标识
DOI:10.1016/j.canlet.2020.06.023
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI