Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism.
Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism.
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垂死的神经胶质瘤细胞通过 caspase 3 依赖性机制建立促血管生成微环境
DOI：
10.1016/j.canlet.2016.10.042
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发表时间：
2017-01-28
期刊：
影响因子：
9.7
通讯作者：
Huang Q
中科院分区：
文献类型：
--
作者：
Feng X;Yu Y;He S;Cheng J;Gong Y;Zhang Z;Yang X;Xu B;Liu X;Li CY;Tian L;Huang Q
放射治疗后血管恢复或再血管生成在肿瘤复发中起重要作用，但这一过程的分子机制仍不清楚。在这项工作中，我们发现死亡的胶质瘤细胞通过caspase3依赖的机制促进照射后血管生成。体外和体内证据表明，抑制caspase3破坏了濒临死亡的胶质瘤细胞的促血管生成作用。胶质瘤细胞中caspase3的蛋白水解性失活降低了致瘤性。重要的是，我们确定了NF-κB/COX-2/PGE2轴作为caspase3的下游信号，介导了辐射后的促血管生成反应。此外，caspase3可能通过磷酸化的eIF4E调节的VEGF-A也被认为是参与促血管生成反应的另一个下游因子。综上所述，Caspase3可能通过调控NF-κB/COX-2/PGE_2轴和p-eIF4E/VEGFA信号通路来支持照射后的促血管生成反应。虽然诱导caspase3的激活一直是肿瘤治疗中普遍采用的概念，但我们的研究反直观地表明，濒死的胶质瘤细胞中caspase3的激活不利于辐射后的血管生成，提示放射治疗联合caspase3抑制剂可能是更有效的策略，因为辐射后的血管生成受到限制。
Vascular recovery or re-angiogenesis after radiotherapy plays a significant role in tumor recurrence, whereas molecular mechanisms of this process remain elusive. In this work, we found that dying glioma cells promoted post-irradiation angiogenesis through a caspase 3 dependent mechanism. Evidence in vitro and in vivo indicated that caspase 3 inhibition undermined proangiogenic effects of dying glioma cells. Proteolytic inactivation of caspase 3 in glioma cells reduced tumorigenicity. Importantly, we identified that NF-κB/COX-2/PGE2 axis acted as downstream signaling of caspase 3, mediating proangiogenic response after irradiation. Additionally, VEGF-A, regulated by caspase 3 possibly through phosphorylated eIF4E, was recognized as another downstream factor participating in the proangiogenic response. In conclusion, these data demonstrated that caspase 3 in dying glioma cells supported the proangiogenic response after irradiation by governing NF-κB/COX-2/PGE2 axis and p-eIF4E/VEGF-A signaling. While inducing caspase 3 activation has been a generally-adopted notion in cancer therapeutics, our study counterintuitively illustrated that caspase 3 activation in dying glioma cells unfavorably supported post-irradiation angiogenesis, suggesting that radiotherapy combined with caspase 3 inhibitors may be more effective strategies due to restricted post-irradiation angiogenesis.