PLSCR1/IP3R1/Ca(2+) axis contributes to differentiation of primary AML cells induced by wogonoside.
PLSCR1/IP3R1/Ca(2+) axis contributes to differentiation of primary AML cells induced by wogonoside.
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PLSCR1/IP3R1/Ca2轴有助于汉黄芩苷诱导的原代AML细胞分化
DOI：
10.1038/cddis.2017.175
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发表时间：
2017-05-11
影响因子：
9
通讯作者：
Hui H
中科院分区：
文献类型：
--
作者：
Li H;Xu J;Zhou Y;Liu X;Shen LE;Zhu YU;Li Z;Wang X;Guo Q;Hui H
多种证据表明，磷脂扰码酶1（PLSCR 1）的表达增加参与了几种分化诱导剂，包括全反式维甲酸和佛波醇12-肉豆蔻酸酯13-乙酸酯的急性髓性白血病（AML）细胞的分化。然而，这些试剂都不能实现PLSCR 1的非均匀亚细胞分布。我们已经证明汉黄芩苷通过促进PLSCR 1进入细胞核而在AML细胞系中具有分化和抗白血病作用。在这里，我们报告汉黄芩苷促进表达PLSCR 1，并增强其核转位和结合的1，4，5-三磷酸受体1（IP 3R 1）启动子在AML患者源性原代细胞。汉黄芩苷激活IP 3R 1，促进内质网Ca 2+释放，最终导致细胞分化。我们的体内研究进一步证实，汉黄芩苷可以促进原代AML细胞中PLSCR 1和IP 3R 1的表达，并减少移植的非肥胖糖尿病/严重联合免疫缺陷小鼠的AML细胞计数。总之，我们的研究结果提供了新的见解的机制，汉黄芩苷诱导分化和对原代AML细胞的抗白血病作用，表明汉黄芩苷对AML的治疗潜力，特别是对非APL AML。
Multiple lines of evidence have demonstrated that increased expression of phospholipid scramblase 1 (PLSCR1) is involved in the differentiation of acute myeloid leukemia (AML) cells by several differentiation-inducing agents including ATRA and phorbol 12-myristate 13-acetate. However, none of these agents can achieve nonhomogenous subcellular distribution of PLSCR1. We have demonstrated that wogonoside possesses differentiation and anti-leukemic effects in AML cell lines by promoting PLSCR1 trafficking into nucleus. Here we report that wogonoside promotes the expression of PLSCR1 and enhances its nuclear translocation and binding to the 1, 4, 5-trisphosphate receptor 1 (IP3R1) promoter in AML patient-derived primary cells. Wogonoside activates IP3R1, in turn, promotes release of Ca 2+ from endoplasmic reticulum, and eventually leads to cell differentiation. Our in vivo study further confirms that wogonoside can promote PLSCR1 and IP3R1 expression in primary AML cells and reduce the AML cell counts in engrafted nonobese diabetic/severe combined immunodeficient mice. Taken together, our findings provide new insight into the mechanism of wogonoside-induced differentiation and anti-leukemic effect on primary AML cells, suggesting the therapeutic potential of wogonoside for AML, especially for non-APL AML.
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