Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA.
Cancer Biol Ther. 2011 Jan 1;11(1):32-9. doi: 10.4161/cbt.11.1.13835.
Glioblastomas continue to carry poor prognoses for patients despite advances in surgical, chemotherapeutic, and radiation regimens. One feature of glioblastoma associated with poor prognosis is the degree of hypoxia and expression levels of hypoxia-inducible factor-1 α (HIF-1α). HIF-1α expression allows metabolic adaptation to low oxygen availability, partly through upregulation of VEGF and increased tumor angiogenesis. Here, we demonstrate an induced level of astrocyte-elevated gene-1 (AEG-1) by hypoxia in glioblastoma cells. AEG-1 has the capacity to promote anchorage-independent growth and cooperates with Ha-ras in malignant transformation. In addition, AEG-1 was recently demonstrated to serve as an oncogene and can induce angiogenesis in glioblastoma. Results from in vitro studies show that hypoxic induction of AEG-1 is dependent on HIF-1α stabilization during hypoxia and that PI3K inhibition abrogates AEG-1 induction during hypoxia through loss of HIF-1α stability. Furthermore, we show that AEG-1 is induced by glucose deprivation and that prevention of intracellular reactive oxygen species (ROS) production prevents this induction. Additionally, AEG-1 knockdown results in increased ROS production and increased glucose deprivation-induced cytotoxicity. On the other hand, AEG-1 overexpression prevents ROS production and decreases glucose deprivation-induced cytotoxicity, indicating that AEG-1 induction is necessary for cells to survive this type of cell stress. These observations link AEG-1 overexpression in glioblastoma with hypoxia and glucose deprivation, and targeting these physiological pathways may lead to therapeutic advances in the treatment of glioblastoma in the future.
尽管在手术、化疗和放疗方案方面取得了进展，但胶质母细胞瘤患者的预后仍然不佳。与预后不良相关的胶质母细胞瘤的一个特征是缺氧程度和缺氧诱导因子-1α（HIF-1α）的表达水平。HIF-1α 的表达允许代谢适应低氧供应，部分通过上调 VEGF 和增加肿瘤血管生成。在这里，我们在胶质母细胞瘤细胞中证明了缺氧诱导的星形细胞上调基因-1（AEG-1）的诱导水平。AEG-1 具有促进锚定独立生长的能力，并与 Ha-ras 协同促进恶性转化。此外，最近发现 AEG-1 作为一种癌基因，可以诱导胶质母细胞瘤中的血管生成。体外研究结果表明，AEG-1 的缺氧诱导依赖于缺氧期间 HIF-1α 的稳定，并且 PI3K 抑制通过 HIF-1α 稳定性丧失来阻断缺氧期间 AEG-1 的诱导。此外，我们表明 AEG-1 是由葡萄糖剥夺诱导的，并且防止细胞内活性氧（ROS）的产生可防止这种诱导。此外，AEG-1 敲低会导致 ROS 产生增加和葡萄糖剥夺诱导的细胞毒性增加。另一方面，AEG-1 的过表达可防止 ROS 的产生并降低葡萄糖剥夺诱导的细胞毒性，表明 AEG-1 的诱导对于细胞在这种细胞应激下存活是必需的。这些观察结果将胶质母细胞瘤中的 AEG-1 过表达与缺氧和葡萄糖剥夺联系起来，针对这些生理途径可能会导致未来胶质母细胞瘤治疗的治疗进展。
