Diptoindonesin G promotes ERK-mediated nuclear translocation of p-STAT1 (Ser727) and cell differentiation in AML cells.
Diptoindonesin G promotes ERK-mediated nuclear translocation of p-STAT1 (Ser727) and cell differentiation in AML cells.
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Diptoindonesin G 促进 ERK 介导的 p-STAT1 (Ser727) 核转位和 AML 细胞的细胞分化
DOI：
10.1038/cddis.2017.159
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发表时间：
2017-05-04
影响因子：
9
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Gao J;Fan M;Xiang G;Wang J;Zhang X;Guo W;Wu X;Sun Y;Gu Y;Ge H;Tan R;Qiu H;Shen Y;Xu Q
探索一种新的分化治疗方法，扩大急性髓细胞白血病（AML）的分化范围，是研究人员和临床医生的吸引力。在这里，我们报告，二氢吲哚甘油醚G（Dip G），一种天然的白藜芦醇非整倍体，通过诱导AML细胞系和原代AML细胞的G2/M期阻滞和细胞分化发挥抗增殖活性。基因分析实验表明，用Dip G处理人白血病HL-60细胞与STAT 1靶基因表达的显著上调相关，包括IFIT 3和CXCL 10。在机制上，Dip G激活ERK，导致STAT 1在Ser 727处磷酸化，并选择性地增强p-STAT 1（Ser 727）和p-ERK的相互作用，进一步促进它们的核转位。p-STAT 1和p-ERK的核转位增强了AML细胞中STAT 1靶向基因的反式激活。此外，HL-60异种移植物的体内治疗表明，Dip G通过诱导细胞分化显著抑制肿瘤生长并降低肿瘤重量。综上所述，这些结果揭示了ERK介导的p-STAT 1（Ser 727）的核转位及其在Dip G诱导的AML细胞分化中的完整转录活性的重要作用。此外，这些结果表明，Dip G可用作AML治疗的分化诱导剂，特别是用于非急性早幼粒细胞白血病治疗。
Exploration of a new differentiation therapy that extends the range of differentiation for treating acute myeloid leukemia (AML) is attractive to researchers and clinicians. Here we report that diptoindonesin G (Dip G), a natural resveratrol aneuploid, exerts antiproliferative activity by inducing G2/M phase arrest and cell differentiation in AML cell lines and primary AML cells. Gene-profiling experiments showed that treating human leukemia HL-60 cells with Dip G was associated with a remarkable upregulation of STAT1 target gene expression, including IFIT3 and CXCL10. Mechanistically, Dip G activated ERK, which caused phosphorylation of STAT1 at Ser727 and selectively enhanced the interaction of p-STAT1 (Ser727) and p-ERK, further promoting their nuclear translocation. The nuclear translocation of p-STAT1 and p-ERK enhanced the transactivation of STAT1-targeted genes in AML cells. Furthermore, in vivo treatment of HL-60 xenografts demonstrated that Dip G significantly inhibited tumor growth and reduced tumor weight by inducing cell differentiation. Taken together, these results shed light on an essential role for ERK-mediated nuclear translocation of p-STAT1 (Ser727) and its full transcriptional activity in Dip G-induced differentiation of AML cells. Furthermore, these results demonstrate that Dip G could be used as a differentiation-inducing agent for AML therapy, particularly for non-acute promyelocytic leukemia therapy.
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