Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
Biochem Pharmacol. 2014 Jun 15;89(4):477-89. doi: 10.1016/j.bcp.2014.04.014. Epub 2014 Apr 30.
Glioblastoma multiforme (GBM) is a life-threatening brain tumor with fatal recurrence, for which glioblastoma stem cells (GSCs) are held responsible. Though endothelial-monocyte activating polypeptide-II (EMAP-II) has been confirmed as a possible antitumor agent that can induce apoptosis of endothelial cells and inhibit tumor angiogenesis, the direct cytotoxicity by EMAP-II on tumor cells and its underlying mechanism are largely unknown. In the present study, it was demonstrated that low-dose (0.05 nM) EMAP-II reduces cell viability and mitochondrial membrane potential in vitro. Likewise, EMAP-II suppressed tumor growth in GSC-xenografted mice. Though no apoptosis was detected, all these antitumor effects were attenuated when GSCs were pretreated with 3-methyladenine (3-MA). Analysis of EMAP-II-treated GSCs exhibited the morphological and biochemical changes typical of autophagy, which was further shown to be defective. Moreover, EMAP-II was found to suppress tumor growth by inducing G2/M arrest in GSCs. Our data further showed that EMAP-II inhibited PI3K/Akt activation with concomitant induction of FoxO1 activation. FoxO1 knockdown significantly attenuated the induction of autophagy and G2/M arrest. Excessive accumulation of lipid droplets was intriguingly detected by transmission electron microscope, which was accompanied by autophagosomes. Further investigation indicated that the transcriptional regulation of Atg2B by FoxO1 was responsible for the induction of autophagy and formation of lipid droplets. These results suggest that EMAP-II is an effective anticancer agent for glioblastoma therapy, which can induce direct growth suppression in GSCs through defective autophagy and G2/M arrest mediated by the PI3K/Akt/FoxO1 axis.
多形性胶质母细胞瘤（GBM）是一种危及生命的脑肿瘤，具有致命的复发率，胶质母细胞瘤干细胞（GSCs）为此负责。虽然内皮细胞-单核细胞激活肽-II（EMAP-II）已被确认为一种可能的抗肿瘤药物，可诱导内皮细胞凋亡并抑制肿瘤血管生成，但 EMAP-II 对肿瘤细胞的直接细胞毒性及其潜在机制在很大程度上尚不清楚。在本研究中，证明低剂量（0.05 nM）EMAP-II 在体外降低细胞活力和线粒体膜电位。同样，EMAP-II 抑制 GSC 异种移植小鼠的肿瘤生长。虽然没有检测到细胞凋亡，但当 GSCs 用 3-甲基腺嘌呤（3-MA）预处理时，所有这些抗肿瘤作用都减弱。对 EMAP-II 处理的 GSCs 的分析显示出典型的自噬形态和生化变化，进一步表明自噬缺陷。此外，发现 EMAP-II 通过诱导 GSCs 中的 G2/M 期阻滞来抑制肿瘤生长。我们的数据进一步表明，EMAP-II 抑制 PI3K/Akt 激活，同时诱导 FoxO1 激活。FoxO1 敲低显著减弱了自噬和 G2/M 期阻滞的诱导。透射电子显微镜检测到令人惊讶的脂滴过度积累，伴有自噬体。进一步的研究表明，FoxO1 对 Atg2B 的转录调控负责自噬和脂滴的形成。这些结果表明，EMAP-II 是胶质母细胞瘤治疗的有效抗癌药物，可通过 PI3K/Akt/FoxO1 轴介导的缺陷自噬和 G2/M 期阻滞直接抑制 GSCs 的生长。
