Drogat Benjamin, Auguste Patrick, Nguyen Duc Thang, Bouchecareilh Marion, Pineau Raphael, Nalbantoglu Josephine, Kaufman Randal J, Chevet Eric, Bikfalvi Andréas, Moenner Michel
INSERM E0113, Université Bordeaux I, Bâtiment B2, Avenue des Facultes, Falence F-33400, France.
Cancer Res. 2007 Jul 15;67(14):6700-7. doi: 10.1158/0008-5472.CAN-06-3235.
In solid tumors, cancer cells subjected to ischemic conditions trigger distinct signaling pathways contributing to angiogenic stimulation and tumor development. Characteristic features of tumor ischemia include hypoxia and glucose deprivation, leading to the activation of hypoxia-inducible factor-1-dependent signaling pathways and to complex signaling events known as the unfolded protein response. Here, we show that the activation of the endoplasmic reticulum stress sensor IRE1 is a common determinant linking hypoxia- and hypoglycemia-dependent responses to the up-regulation of vascular endothelial growth factor-A (VEGF-A). Tumor cells expressing a dominant-negative IRE1 transgene as well as Ire1alpha-null mouse embryonic fibroblasts were unable to trigger VEGF-A up-regulation upon either oxygen or glucose deprivation. These data correlated with a reduction of tumor angiogenesis and growth in vivo. Our results therefore suggest an essential role for IRE1-dependent signaling pathways in response to ischemia and identify this protein as a potential therapeutic target to control both the angiogenic switch and tumor development.
在实体瘤中，处于缺血状态的癌细胞会触发不同的信号通路，促进血管生成刺激和肿瘤发展。肿瘤缺血的特征包括缺氧和葡萄糖剥夺，导致缺氧诱导因子-1依赖性信号通路的激活以及被称为未折叠蛋白反应的复杂信号事件。在此，我们表明内质网应激传感器IRE1的激活是一个共同的决定因素，它将缺氧和低血糖依赖性反应与血管内皮生长因子-A（VEGF-A）的上调联系起来。表达显性负性IRE1转基因的肿瘤细胞以及Ire1α基因敲除的小鼠胚胎成纤维细胞在缺氧或葡萄糖剥夺时均无法触发VEGF-A的上调。这些数据与体内肿瘤血管生成和生长的减少相关。因此，我们的结果表明IRE1依赖性信号通路在对缺血的反应中起重要作用，并将该蛋白确定为控制血管生成开关和肿瘤发展的潜在治疗靶点。
