Maachani Uday B, Shankavaram Uma, Kramp Tamalee, Tofilon Philip J, Camphausen Kevin, Tandle Anita T
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Oncotarget. 2016 Nov 22;7(47):77365-77377. doi: 10.18632/oncotarget.12670.
Glioblastoma multiforme (GBM) continues to be the most frequently diagnosed and lethal primary brain tumor. Adjuvant chemo-radiotherapy remains the standard of care following surgical resection. In this study, using reverse phase protein arrays (RPPAs), we assessed the biological effects of radiation on signaling pathways to identify potential radiosensitizing molecular targets. We identified subsets of proteins with clearly concordant/discordant behavior between irradiated and non-irradiated GBM cells in vitro and in vivo. Moreover, we observed high expression of Forkhead box protein M1 (FOXM1) in irradiated GBM cells both in vitro and in vivo. Recent evidence of FOXM1 as a master regulator of metastasis and its important role in maintaining neural, progenitor, and GBM stem cells, intrigued us to validate it as a radiosensitizing target. Here we show that FOXM1 inhibition radiosensitizes GBM cells by abrogating genes associated with cell cycle progression and DNA repair, suggesting its role in cellular response to radiation. Further, we demonstrate that radiation induced stimulation of FOXM1 expression is dependent on STAT3 activation. Co-immunoprecipitation and co-localization assays revealed physical interaction of FOXM1 with phosphorylated STAT3 under radiation treatment. In conclusion, we hypothesize that FOXM1 regulates radioresistance via STAT3 in GBM cells. We also, show GBM patients with high FOXM1 expression have poor prognosis. Collectively our observations might open novel opportunities for targeting FOXM1 for effective GBM therapy.
多形性胶质母细胞瘤（GBM）仍然是最常被诊断出且致死率最高的原发性脑肿瘤。辅助放化疗仍然是手术切除后的标准治疗方法。在本研究中，我们使用反相蛋白质阵列（RPPA）评估了辐射对信号通路的生物学效应，以确定潜在的放射增敏分子靶点。我们在体外和体内确定了受辐照和未受辐照的GBM细胞之间具有明显一致/不一致行为的蛋白质亚群。此外，我们在体外和体内的受辐照GBM细胞中均观察到叉头框蛋白M1（FOXM1）的高表达。最近有证据表明FOXM1是转移的主要调节因子，并且在维持神经、祖细胞和GBM干细胞中起重要作用，这促使我们将其验证为放射增敏靶点。在这里，我们表明抑制FOXM1可通过消除与细胞周期进程和DNA修复相关的基因使GBM细胞对辐射敏感，这表明其在细胞对辐射的反应中起作用。此外，我们证明辐射诱导的FOXM1表达刺激依赖于STAT3激活。免疫共沉淀和共定位分析揭示了在辐射处理下FOXM1与磷酸化STAT3之间的物理相互作用。总之，我们假设FOXM1在GBM细胞中通过STAT3调节放射抗性。我们还表明，FOXM1高表达的GBM患者预后较差。我们的观察结果共同可能为靶向FOXM1进行有效的GBM治疗开辟新的机会。
