Tumour Biology Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, College Road, Cork, Ireland.
Leuk Res. 2013 Feb;37(2):183-9. doi: 10.1016/j.leukres.2012.11.003. Epub 2012 Dec 3.
Constitutive expression of the Bcr-Abl kinase in Chronic Myelogenous Leukaemia (CML) is known to produce elevated levels of Reactive Oxygen Species (ROS) which can enhance cell survival as well as generate genomic instability. Our laboratory has previously demonstrated that NADPH oxidase (Nox) activity contributes to intracellular-ROS levels in Bcr-Abl-positive cells, while inducing increased pro-survival signalling through the PI3K/Akt pathway. How Bcr-Abl signalling regulates Nox activity still remains to be elucidated. In this study, using the K562 CML cell line we showed that inhibition of Bcr-Abl signalling, by either Imatinib or Nilotinib, led to a significant reduction in ROS levels which was concurrent with the GSK-3β dependent, post-translational down-regulation of the small membrane-bound protein p22phox, an essential component of the Nox complex. Furthermore, siRNA knockdown of p22phox in these cells established its importance in ROS production and proliferation. Taken together we believe our results provide a possible link between Bcr-Abl signalling and ROS production through Nox activity and demonstrate a novel mechanism of action associated with Imatinib and Nilotinib treatment in CML.
Bcr-Abl 激酶在慢性髓性白血病（CML）中的组成型表达已知会产生高水平的活性氧（ROS），这可以增强细胞存活并产生基因组不稳定性。我们的实验室之前已经证明，NADPH 氧化酶（Nox）活性有助于 Bcr-Abl 阳性细胞中的细胞内 ROS 水平，同时通过 PI3K/Akt 途径诱导增加的生存信号。Bcr-Abl 信号如何调节 Nox 活性仍有待阐明。在这项研究中，我们使用 K562 CML 细胞系表明，通过伊马替尼或尼罗替尼抑制 Bcr-Abl 信号会导致 ROS 水平显著降低，这与 GSK-3β 依赖性、翻译后小膜结合蛋白 p22phox 的下调有关，p22phox 是 Nox 复合物的一个重要组成部分。此外，在这些细胞中用 p22phox 的 siRNA 敲低确立了其在 ROS 产生和增殖中的重要性。综上所述，我们相信我们的结果提供了 Bcr-Abl 信号和 ROS 产生之间通过 Nox 活性的可能联系，并证明了与 CML 中伊马替尼和尼罗替尼治疗相关的一种新的作用机制。
