Membranous NOX5-derived ROS oxidizes and activates local Src to promote malignancy of tumor cells
Membranous NOX5-derived ROS oxidizes and activates local Src to promote malignancy of tumor cells
复制标题
膜NOX5衍生ROS氧化并激活局部Src促进肿瘤细胞恶性
DOI：
10.1038/s41392-020-0193-z
复制
发表时间：
2020-08-14
影响因子：
39.3
通讯作者：
Zhan, Qimin
中科院分区：
文献类型：
--
作者：
Chen, Jie;Wang, Yan;Zhan, Qimin
位于精确亚细胞区室的活性氧（ROS）对调节信号蛋白的活性至关重要。此外，活性氧是肿瘤恶性进展的主要调节因子，对多种环境应激，特别是缺氧作出反应。NADPH氧化酶（NOXs）似乎在离散的亚细胞区室中被激活，以促进局部ROS的产生。然而，NOXs在缺氧肿瘤中的亚细胞功能尚不清楚。在本研究中，我们发现NOX5在临床食管鳞状细胞癌（ESCC）肿瘤、ESCC细胞系或原代ESCC细胞中表达显著上调，且NOX5的升高与ESCC肿瘤的恶性和不良预后相关。NOX5通过激活Src诱导ESCC恶性进展，特别是在缺氧条件下。在机制上，我们发现缺氧通过促进Ca2+介导的Pyk2 tyr402位点磷酸化促进了NOX5和细胞膜上Pyk2的相互作用。随后，Pyk2作为c-Abl磷酸化NOX5 tyr476 /478位点催化结构域的支架，从而上调Pyk2/NOX5复合物内的过氧化氢（H2O2）氧化并激活局部Src。这些发现为NOX5在ESCC发展中的生物学意义提供了见解。
Reactive oxygen species (ROS) localized at the precise subcellular compartments are essential for regulating the activity of signaling proteins. Furthermore, ROS are master regulators of tumor malignant progression that respond to a diverse set of environmental stress, especially hypoxia. NADPH oxidases (NOXs) appear to be activated within discrete subcellular compartments to facilitate local ROS production. However, the subcellular function of NOXs in hypoxic tumor is still unclear. In this study, we demonstrated that NOX5 was greatly upregulated in clinical esophageal squamous cell carcinoma (ESCC) tumors, ESCC cell lines or primary ESCC cells, and elevated NOX5 was correlated to malignancy of ESCC tumors and poor prognosis. NOX5 induced the malignant progression of ESCC by activating Src, especially under hypoxic condition. Mechanistically, we showed that hypoxia promoted the interaction between NOX5 and Pyk2 on cell membrane via facilitating Ca2+-mediated Pyk2 Tyr402site phosphorylation. Subsequently, Pyk2 acted as a scaffold for c-Abl phosphorylating the catalytic domain of NOX5 Tyr476/478sites, which in turn upregulated hydrogen peroxide (H2O2) inside the Pyk2/NOX5 complex to oxidize and activate local Src. These findings provide insights into the biological significance of NOX5 in the development of ESCC.