Anti-leukemia activity of NSC-743380 in SULT1A1-expressing acute myeloid leukemia cells is associated with inhibitions of cFLIP expression and PI3K/AKT/mTOR activities.
Anti-leukemia activity of NSC-743380 in SULT1A1-expressing acute myeloid leukemia cells is associated with inhibitions of cFLIP expression and PI3K/AKT/mTOR activities.
复制标题
DOI：
10.18632/oncotarget.22235
复制
发表时间：
2017-11-24
期刊：
影响因子：
--
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Huang X;Cao M;Wu S;Wang L;Hu J;Mehran RJ;Roth JA;Swisher SG;Wang RY;Kantarjian HM;Andreeff M;Sun X;Fang B
我们最近的研究表明，表达SULT1A1的急性髓性白血病（AML）细胞对NSC-743380高度敏感，NSC-743380是一种抑制STAT3活性并诱导多种癌细胞依赖SULT1A1凋亡的小分子。在这项研究中，我们表征了NSC-743380在AML细胞系中介导的抗白血病活性的分子机制，以及NSC-743380在AML患者源性原发性白血病细胞中的抗白血病活性。我们的研究结果表明，NSC-743380在sult1a1阳性的AML细胞中引发了强烈的凋亡。NSC-743380治疗并没有增加AML细胞内活性氧或改变STAT3活性，但却显著且迅速地降低了cFLIP的表达。反相蛋白芯片的蛋白质组学分析显示，NSC-743380处理U937和THP-1 AML细胞导致PI3K/AKT/mTOR通路中几个关键节点磷酸化的剧烈和时间依赖性抑制，包括AKT和mTOR。此外，表达SULT1A1的原代AML细胞对NSC-743380治疗高度敏感，而与骨髓间充质干细胞共培养不受影响。因此，我们的研究结果提供了概念验证证据，表明表达SULT1A1的AML细胞可以被小分子靶向，通过抑制多个靶点的表达或活性诱导细胞凋亡。
Our recent study showed that acute myeloid leukemia (AML) cells expressing SULT1A1 are highly sensitive to NSC-743380, a small molecule that inhibits STAT3 activity and induces SULT1A1-dependent apoptosis of various cancer cell lines. In this study, we characterized the molecular mechanisms of NSC-743380–mediated anti-leukemia activity in AML cell lines and antileukemia activity of NSC-743380 in patient-derived primary leukemia cells from AML patients. Our results showed that treatment with NSC-743380 triggered robust apoptosis in SULT1A1-positive AML cells. Treatment with NSC-743380 did not increase intracellular reactive oxygen species or change of STAT3 activity in AML cells, but did dramatically and rapidly decrease cFLIP expression. Proteomic analysis with reverse phase protein microarray revealed that treatment of U937 and THP-1 AML cells with NSC-743380 led to drastic and time-dependent suppression of phosphorylation of several key nodes in the PI3K/AKT/mTOR pathway, including AKT and mTOR. Moreover, primary AML cells expressed SULT1A1 were highly sensitive to treatment with NSC-743380, which was not affected by co-culture with bone marrow mesenchymal stem cells. Thus, our results provide proof-of-concept evidence that AML cells expressing SULT1A1 can be targeted by small molecules that induce apoptosis through inhibiting the expression or activities of multiple targets.
登录
查看更多内容
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
影响因子：
20.3
作者：
Ben-Batalla, Isabel;Schultze, Alexander;Loges, Sonja
通讯作者：
Loges, Sonja
影响因子：
8.8
作者：
Panayotova-Dimitrova, Diana;Feoktistova, Maria;Leverkus, Martin
通讯作者：
Leverkus, Martin
影响因子：
15.3
作者：
Medema, J P;de Jong, J;van Hall, T;Melief, C J;Offringa, R
通讯作者：
Offringa, R
肺癌信号转导和 DNA 修复途径相关蛋白的异常表达及其与临床参数的关系
影响因子：
3.7
作者：
He Y;Zhou Z;Hofstetter WL;Zhou Y;Hu W;Guo C;Wang L;Guo W;Pataer A;Correa AM;Lu Y;Wang J;Diao L;Byers LA;Wistuba II;Roth JA;Swisher SG;Heymach JV;Fang B
通讯作者：
Fang B