Nox4 redox regulation of PTP1B contributes to the proliferation and migration of glioblastoma cells by modulating tyrosine phosphorylation of coronin-1C
Nox4 redox regulation of PTP1B contributes to the proliferation and migration of glioblastoma cells by modulating tyrosine phosphorylation of coronin-1C
复制标题
DOI：
10.1016/j.freeradbiomed.2013.11.005
复制
发表时间：
2014-02-01
影响因子：
7.4
通讯作者：
Kamata, Tohru
中科院分区：
文献类型：
--
作者：
Mondol, Abdus S.;Tonks, Nicholas K.;Kamata, Tohru
多形性胶质母细胞瘤是成人常见的原发脑瘤，也是人类最具破坏性的癌症之一。近年来，NADPH氧化酶(NOX)4产生的活性氧(ROS)已成为胶质母细胞瘤研究的热点，但NOX4作用的分子机制仍不清楚。在这项研究中，我们证明了NOX4靶向siRNA沉默NOX4的表达抑制了胶质母细胞瘤U87细胞的生长和运动，表明NOX4参与了这一过程。此外，NOX4衍生的ROS被氧化和失活的蛋白酪氨酸磷酸酶(PTP)：1B：PTP1B以其活性形式下调细胞的增殖和迁移。经底物捕获突变体PTP1B亲和纯化，确定酪氨酸磷酸化的冠状病毒1C为PTP1B的底物。其酪氨酸磷酸化水平受NOX4抑制，提示其酪氨酸磷酸化受NOX4-PTP1B途径的调节。最后，去甲肾上腺素-1C减弱了细胞的增殖和迁移活性。综上所述，这些发现揭示了NOX4介导的PTP1B的氧化还原调节部分通过Cortin-1C调节胶质母细胞瘤细胞的生长和迁移，并为了解胶质母细胞瘤恶性的机制提供了新的见解。(C)2013 Elsevier Inc.保留所有权利。
Glioblastoma multiforme is a common primary brain tumor in adults and one of the most devastating human cancers. Reactive oxygen species (ROS) generated by NADPH oxidase (Nox) 4 have recently been a focus of attention in the study of glioblastomas, but the molecular mechanisms underlying the actions of Nox4 remain elusive. In this study, we demonstrated that silencing of Nox4 expression by Nox4-targeted siRNA suppressed cell growth and motility of glioblastoma U87 cells, indicating the involvement of Nox4. Furthermore, Nox4-derived ROS oxidized and inactivated protein tyrosine phosphatase (PTP):1B: PTP1B in its active form downregulates cell proliferation and migration. By affinity purification with the substrate-trapping mutant of PTP1B, tyrosine-phosphorylated coronin-1C was identified as a substrate of PTP1B. Its tyrosine phosphorylation level was suppressed by Nox4 inhibition, suggesting that tyrosine phosphorylation of coronin-1C is regulated by the Nox4-PTP1B pathway. Finally, ablation of coronin-1C attenuated the proliferative and migratory activity of the cells. Collectively, these findings reveal that Nox4-mediated redox regulation of PTP1B serves as a modulator, in part through coronin-1C, of the growth and migration of glioblastoma cells, and provide new insight into the mechanistic aspect of glioblastoma malignancy. (C) 2013 Elsevier Inc. All rights reserved.