Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an 710061, Shaanxi, China; Department of Neurosurgery, Yulin First Hospital Affiliated to Xi'an Jiao Tong University, Yulin 719000, Shaanxi, China.
Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an 710061, Shaanxi, China.
Biomed Pharmacother. 2017 Aug;92:347-355. doi: 10.1016/j.biopha.2017.05.074. Epub 2017 May 26.
Glioma is the most common primary malignant tumor of the central nervous system. B10 is a new glycosylated derivative of betulinic acid with enhanced cytotoxic activity. The present study was designed to explore the molecular mechanism underlying the anticancer effect of B10 in glioma cells. 25-50μM B10 resulted in a significant decrease of cell viability and BrdU incorporation. 25-50mg/kg B10 significantly reduced the implanted tumor weight and volume in nude mice. Activation of apoptosis was found in glioma cells when the cells were exposed to B10, as evidenced by increased number of TUNEL-stained cells, increased caspase 3 and 9 activities, and Bax and cleaved PARP expression. B10 caused a significant decrease in mitochondrial oxygen consumption rate, mitochondrial complex I, II, III, IV, and V activities, and ATP level, and increase of mitochondrial ROS production, indicating the induction of mitochondrial dysfunction. B10 reduced the expression of sirtuin (SIRT) 1 and resulted in an increase in forkhead box O (FOXO) 3a expression and acetylation. Activation of SIRT1 by SRT-1720 and downregualtion of FOXO3a using shRNA significantly inhibited B10-induced cytotoxicity. B10 markedly increased the expression of Bim and PUMA. Downregualtion of FOXO3a or activation of SIRT1 significantly inhibited B10-induced increase of Bim and PUMA expression. Downregualtion of Bim or PUMA could suppress B10-induced increase of Bax expression. Moreover, B10-induced cytotoxicity was significantly suppressed by downregulation of Bim or PUMA. In summary, we identified B10 as a potent therapeutic candidate for glioma treatment and SIRT1-FOXO3a-Bim/PUMA axis as a novel therapeutic target.
神经胶质瘤是中枢神经系统最常见的原发性恶性肿瘤。B10 是白桦脂酸的一种新的糖基化衍生物，具有增强的细胞毒性活性。本研究旨在探讨 B10 在神经胶质瘤细胞中抗癌作用的分子机制。25-50μM 的 B10 导致细胞活力和 BrdU 掺入显著下降。25-50mg/kg 的 B10 显著降低了裸鼠植入肿瘤的重量和体积。当细胞暴露于 B10 时，发现神经胶质瘤细胞发生凋亡激活，表现为 TUNEL 染色细胞数量增加、 caspase 3 和 9 活性增加以及 Bax 和 cleaved PARP 表达增加。B10 导致线粒体耗氧率、线粒体复合物 I、II、III、IV 和 V 活性以及 ATP 水平显著下降，线粒体 ROS 产生增加，表明诱导了线粒体功能障碍。B10 降低了沉默调节蛋白（SIRT）1 的表达，导致叉头框 O（FOXO）3a 表达和乙酰化增加。SIRT1 的激活剂 SRT-1720 和 FOXO3a 的下调 shRNA 显著抑制了 B10 诱导的细胞毒性。B10 显著增加了 Bim 和 PUMA 的表达。FOXO3a 的下调或 SIRT1 的激活显著抑制了 B10 诱导的 Bim 和 PUMA 表达增加。FOXO3a 的下调或 SIRT1 的激活显著抑制了 B10 诱导的 Bim 和 PUMA 表达增加。下调 Bim 或 PUMA 可抑制 B10 诱导的 Bax 表达增加。此外，下调 Bim 或 PUMA 显著抑制了 B10 诱导的细胞毒性。总之，我们将 B10 鉴定为治疗神经胶质瘤的有效治疗候选物，并将 SIRT1-FOXO3a-Bim/PUMA 轴鉴定为一种新的治疗靶点。
