Matrine inhibits BCR/ABL mediated ERK/MAPK pathway in human leukemia cells.
Matrine inhibits BCR/ABL mediated ERK/MAPK pathway in human leukemia cells.
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苦参碱抑制人白血病细胞中 BCR/ABL 介导的 ERK/MAPK 通路
DOI：
10.18632/oncotarget.22353
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发表时间：
2017-12-12
期刊：
影响因子：
--
通讯作者：
Zou C
中科院分区：
文献类型：
--
作者：
Ma L;Xu Z;Wang J;Zhu Z;Lin G;Jiang L;Lu X;Zou C
Bcr/abl融合基因及其下游信号通路如RAS/Raf/MAPK、JAK/STAT3、PI3K/AKT在白血病尤其是慢性粒细胞白血病(CML)的恶性转化中起重要作用。我们前期的研究表明，苦参碱可显著抑制人慢性粒细胞白血病K562细胞的增殖，诱导细胞周期停滞于G0/G1期，并促进细胞凋亡。在本研究中，我们利用K562和HL-60细胞株研究了苦参碱抑制白血病细胞生长的分子机制。RT-PCR和Western印迹分析表明，苦参碱可显著抑制K562和HL-60细胞bcr/abl基因的表达。MEK1、ERK1/2及其上游接头分子Shc和SHP2的磷酸化水平显著下调。ERK/MAPK信号通路各组成部分以及Bclxl、Cyclin D1和c-Myc的蛋白和mRNA表达显著降低。相反，苦参碱处理后，细胞周期进程的负调控因子p27的表达增加。以上结果提示，苦参碱抑制K562和HL-60细胞生长与抑制ERK/MAPK和BCR/ABL信号通路有关。在体内实验中，苦参碱显著降低荷瘤小鼠的死亡率，提示苦参碱在体内具有抗白血病作用。
The BCR/ABL fusion gene and its downstream signaling pathways such as Ras/Raf/MAPK, JAK/STAT3, and PI3K/AKT pathways play important roles in malignant transformation of leukemia, especially chronic myelogenous leukemia (CML). Our previous study showed that matrine, an alkaloid extracted from a Chinese herb radix sophorae, significantly inhibited the proliferation of human CML K562cells, induced cell cycle arrest in G0/G1, and promoted cell apoptosis. In the present study, we investigated the molecular mechanism of matrine in the growth inhibition of leukemia cells using K562 and HL-60 cell lines. RT-PCR and Western blot assay demonstrated that the expression of BCR/ABL in K562 and HL-60 cells was significantly inhibited by matrine treatment. Phosphorylation of MEK1, ERK1/2, and their upstream adaptor molecules Shc and SHP2 were significantly downregulated. The protein and mRNA expression of components of the ERK/MAPK signal pathway, and Bcl-xL, Cyclin D1, and c-Myc, were dramatically reduced. Conversely, the expression of p27, a negative regulator of cell cycle progression, increased after matrine treatment. These results indicated that the inhibition of ERK/MAPK and BCR/ABL signaling pathway was associated with matrine’s suppressive effects on the growth of K562 and HL-60 cells. In in vivo study, matrine significantly decreased the mortality rate of tumor-baring mice and suggested that matrine could exert its anti-leukemia effect in vivo.
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