Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis.
Caspase 3 in dying tumor cells mediates post-irradiation angiogenesis.
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垂死肿瘤细胞中的 Caspase 3 介导辐射后血管生成。
DOI：
10.18632/oncotarget.5898
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Huang Q
中科院分区：
文献类型：
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作者：
Feng X;Tian L;Zhang Z;Yu Y;Cheng J;Gong Y;Li CY;Huang Q
细胞毒性放射治疗可诱导肿瘤细胞产生多种促血管生成物质，促进照射后血管生成，是放射治疗失败的主要原因之一。虽然一些研究已经报道了PIA背后的一些机制，但他们还没有描述埋藏在辐射微环境中的开始的促血管生成刺激因素。在这项工作中，我们揭示了辐射诱导的死亡肿瘤细胞通过caspase3依赖的机制促进PIA。通过转导显性-阴性版本使死亡肿瘤细胞中caspase3的蛋白水解性失活，在体外和体内都减弱了促血管生成的作用。此外，抑制caspase3活性还抑制了异种移植瘤模型的肿瘤血管生成和肿瘤形成。重要的是，我们发现血管内皮生长因子-A是一种下游的促血管生成因子，可能通过Akt信号受caspase3调节。总之，这些发现表明，除了在细胞凋亡中扮演关键执行者的角色外，死亡肿瘤细胞中的caspase3可能在驱动辐射后促血管生成反应中发挥核心作用。因此，放疗联合caspase3抑制剂可能是一种新的治疗策略，可以减少由于抑制的PIA而导致的肿瘤复发。
Cytotoxic radiotherapy unfavorably induces tumor cells to generate various proangiogenic substances, promoting post-irradiation angiogenesis (PIA), which is one of major causes of radiotherapy failure. Though several studies have reported some mechanisms behind PIA, they have not yet described the beginning proangiogenic motivator buried in the irradiated microenvironment. In this work, we revealed that dying tumor cells induced by irradiation prompted PIA via a caspase 3 dependent mechanism. Proteolytic inactivation of caspase 3 in dying tumor cells by transducing a dominant-negative version weakened proangiogenic effects in vitro and in vivo. In addition, inhibition of caspase 3 activity suppressed tumor angiogenesis and tumorigenesis in xenograft mouse model. Importantly, we identified vascular endothelial growth factor (VEGF)-A as a downstream proangiogenic factor regulated by caspase 3 possibly through Akt signaling. Collectively, these findings indicated that besides acting as a key executioner in apoptosis, caspase 3 in dying tumor cells may play a central role in driving proangiogenic response after irradiation. Thus, radiotherapy in combination with caspase 3 inhibitors may be a novel promising therapeutic strategy to reduce tumor recurrence due to restrained PIA.