Targeting of AML1-ETO in t(8;21) Leukemia by Oridonin Generates a Tumor Suppressor-Like Protein
Targeting of AML1-ETO in t(8;21) Leukemia by Oridonin Generates a Tumor Suppressor-Like Protein
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冬凌草甲素靶向 t(8;21) 白血病中的 AML1-ETO 生成肿瘤抑制样蛋白
DOI：
10.1126/scitranslmed.3003562
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发表时间：
2012-03-28
影响因子：
17.1
通讯作者：
Chen, Zhu
中科院分区：
文献类型：
--
作者：
Zhen, Tao;Wu, Chuan-Feng;Chen, Zhu
近60%的t（8; 21）（q22; q22）易位的急性髓性白血病（AML）患者不能实现长期无病生存。我们的前期研究表明，冬凌草甲素选择性地诱导t（8; 21）白血病细胞凋亡，并导致t（8; 21）白血病细胞产生的AML 1-ETO癌蛋白裂解，但其机制尚不清楚。我们发现，冬凌草甲素与谷胱甘肽和硫氧还蛋白/硫氧还蛋白还原酶相互作用，增加细胞内活性氧，从而激活t（8; 21）细胞中的caspase-3。冬凌草甲素与AML 1-ETO结合后，通过caspase-3将AML 1-ETO酶切至天冬氨酸188位，形成截短的AML 1-ETO（DAML 1-ETO），阻止AML 1-ETO蛋白进一步水解。DAML 1-ETO与AML 1-ETO相互作用，干扰AML 1-ETO癌蛋白的反式调节功能，从而作为肿瘤抑制因子介导冬凌草甲素的抗白血病作用。此外，冬凌草甲素还能抑制c-Kit+白血病起始细胞的活性。因此，冬凌草甲素是白血病分子靶向治疗的潜在先导化合物。
Nearly 60% of acute myeloid leukemia (AML) patients with the t(8; 21)(q22; q22) translocation fail to achieve longterm disease-free survival. Our previous studies demonstrated that oridonin selectively induces apoptosis of t(8; 21) leukemia cells and causes cleavage of AML1-ETO oncoprotein resulting from t(8; 21), but the underlying mechanisms remain unclear. We show that oridonin interacted with glutathione and thioredoxin/thioredoxin reductase to increase intracellular reactive oxygen species, which in turn activated caspase-3 in t(8; 21) cells. Moreover, oridonin bound AML1-ETO, directing the enzymatic cleavage at aspartic acid 188 via caspase-3 to generate a truncated AML1-ETO (DAML1-ETO) and preventing the protein from further proteolysis. DAML1-ETO interacted with AML1-ETO and interfered with the trans-regulatory functions of remaining AML1-ETO oncoprotein, thus acting as a tumor suppressor that mediates the anti-leukemia effect of oridonin. Furthermore, oridonin inhibited the activity of c-Kit+ leukemia-initiating cells. Therefore, oridonin is a potential lead compound for molecular target-based therapy of leukemia.