Hypoxia-induced angiotensin II by the lactate-chymase-dependent mechanism mediates radioresistance of hypoxic tumor cells.
Hypoxia-induced angiotensin II by the lactate-chymase-dependent mechanism mediates radioresistance of hypoxic tumor cells.
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DOI：
10.1038/srep42396
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Yuan Y
中科院分区：
文献类型：
--
作者：
Xie G;Liu Y;Yao Q;Zheng R;Zhang L;Lin J;Guo Z;Du S;Ren C;Yuan Q;Yuan Y
肾素-血管紧张素系统(RAS)是决定动脉血压和水电解质平衡的主要因素。最近在一些恶性肿瘤中发现了RAS组分失调，并与不良的患者预后相关。然而，肿瘤局部RAS激活的确切机制仍不清楚。在这里，我们发现局部血管紧张素II主要存在于鼻咽癌CNE2细胞和乳腺癌MDA-MB-231细胞形成的肿瘤的缺氧区，这些肿瘤细胞通过乳糜酶依赖而不是血管紧张素转换酶依赖的机制自动分泌血管紧张素II。我们在鼻咽癌CNE2和5-8F细胞中进一步证明，这种依赖于糜酶的效应是通过增加乳酸水平来介导的，乳酸是糖酵解代谢的副产物。最后，我们发现，增强的血管紧张素II在低氧鼻咽癌细胞内HIF-1α的积聚中起重要作用，并介导这些鼻咽癌细胞的辐射耐受表型。因此，我们的发现揭示了低氧通过乳酸-糜酶依赖机制在局部血管紧张素II的产生中的关键作用，并强调了局部血管紧张素II在调节低氧肿瘤细胞辐射抵抗中的重要性。
The renin-angiotensin system (RAS) is a principal determinant of arterial blood pressure and fluid and electrolyte balance. RAS component dysregulation was recently found in some malignancies and correlated with poor patient outcomes. However, the exact mechanism of local RAS activation in tumors is still unclear. Here, we find that the local angiotensin II predominantly exists in the hypoxic regions of tumor formed by nasopharyngeal carcinoma CNE2 cells and breast cancer MDA-MB-231 cells, where these tumor cells autocrinely produce angiotensin II by a chymase-dependent rather than an angiotensin converting enzyme-dependent mechanism. We further demonstrate in nasopharyngeal carcinoma CNE2 and 5–8F cells that this chymase-dependent effect is mediated by increased levels of lactate, a by-product of glycolytic metabolism. Finally, we show that the enhanced angiotensin II plays an important role in the intracellular accumulation of HIF-1α of hypoxic nasopharyngeal carcinoma cells and mediates the radiation-resistant phenotype of these nasopharyngeal carcinoma cells. Thus, our findings reveal the critical role of hypoxia in producing local angiotensin II by a lactate-chymase-dependent mechanism and highlight the importance of local angiotensin II in regulating radioresistance of hypoxic tumor cells.