小 GTP 酶 RalA 的抑制调节慢性髓性白血病 (CML) 细胞的生长和砷诱导的细胞凋亡。

Inhibition of small GTPase RalA regulates growth and arsenic-induced apoptosis in chronic myeloid leukemia (CML) cells.

机构信息

Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.

出版信息

Cell Signal. 2012 Jun;24(6):1134-40. doi: 10.1016/j.cellsig.2012.01.016. Epub 2012 Feb 3.

DOI:10.1016/j.cellsig.2012.01.016

Abstract

Chronic myelogenous leukemia (CML) results from the transformation of a primitive hematopoietic cell by the bcr-abl gene. RalA, one of the Ras superfamily of small GTPases, is a downstream molecule of bcr-abl fusion protein in ras signaling pathway, but its role in CML is poorly understood. Here, we first detected RalA level in CML cells, which is highly expressed and distributed mainly in the cytoplasm and/or partially in endomembrane. Next, siRNA was used to deplete RalA expression for elucidating its function. The results showed that siRNA RalA effectively inhibited cell viability, induced apoptosis and enhanced sensitivity of arsenic trioxide (ATO), and there are some synergistic effects of anti-CML between RalA siRNA and ATO. Finally, we found that ATO also could downregulate protein level of bcr-abl in K562 and KCL-22. Our research provides evidence that RalA might also serve as linchpin modulators in leukemia, and combinatorial therapies of dual inhibition of bcr-abl and ras signaling pathways have a great potential in treatment of CML.

摘要

慢性髓细胞白血病（CML）是由 bcr-abl 基因转化原始造血细胞引起的。RalA 是 Ras 超家族小分子 GTPases 之一，是 ras 信号通路中 bcr-abl 融合蛋白的下游分子，但它在 CML 中的作用尚不清楚。在这里，我们首先检测了 CML 细胞中的 RalA 水平，发现其高度表达，并主要分布在细胞质和/或部分在内膜上。接下来，使用 siRNA 耗尽 RalA 的表达以阐明其功能。结果表明，siRNA RalA 可有效抑制细胞活力，诱导细胞凋亡，并增强三氧化二砷（ATO）的敏感性，而且 RalA siRNA 和 ATO 之间存在抗 CML 的协同作用。最后，我们发现 ATO 还可以下调 K562 和 KCL-22 中 bcr-abl 的蛋白水平。我们的研究提供了证据，表明 RalA 也可能作为白血病的关键调节因子，双重抑制 bcr-abl 和 ras 信号通路的联合治疗在治疗 CML 方面具有巨大潜力。