Rapamycin-resistant and torin-sensitive mTOR signaling promotes the survival and proliferation of leukemic cells.
Rapamycin-resistant and torin-sensitive mTOR signaling promotes the survival and proliferation of leukemic cells.
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DOI：
10.5483/bmbrep.2016.49.1.201
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发表时间：
2016-01
期刊：
影响因子：
3.8
通讯作者：
Lee K
中科院分区：
文献类型：
--
作者：
Park S;Sim H;Lee K
丝氨酸/苏氨酸激酶mTOR是磷酸化肌肽3激酶（PI3K）信号通路的重要组成部分，调控免疫细胞的发育和功能。mTOR信号通路的异常激活与包括白血病在内的许多癌症有关。在这里，我们报告了mTOR信号传导对人类白血病细胞系和小鼠t细胞急性白血病（T-ALL）细胞生长的贡献。Torin是一种atp竞争性mTOR抑制剂，对U-937、THP-1和rpm -8226细胞具有细胞毒性和细胞抑制作用，但对Jurkat和K-562细胞没有作用。即使mTOR复合物1的活性受到抑制，所有细胞都对雷帕霉素具有相对抗性。Notch1诱导的T-ALL细胞的生长受到torin的深刻影响，部分原因是bcl2111和Bbc3的表达增加。值得注意的是，激活Akt或敲低FoxO1可减轻mTOR对T-ALL细胞的抑制作用。我们的数据提供了mTOR抑制剂对白血病细胞存活和增殖的影响，从而进一步提高了我们对mTOR信号传导的细胞环境依赖性影响的理解。[BMB报告2016；49 (1): 63 - 68)
The serine/threonine kinase mTOR is essential for the phosphoinositide 3-kinases (PI3K) signaling pathway, and regulates the development and function of immune cells. Aberrant activation of mTOR signaling pathway is associated with many cancers including leukemia. Here, we report the contributions of mTOR signaling to growth of human leukemic cell lines and mouse T-cell acute leukemia (T-ALL) cells. Torin, an ATP-competitive mTOR inhibitor, was found to have both cytotoxic and cytostatic effects on U-937, THP-1, and RPMI-8226 cells, but not on Jurkat or K-562 cells. All cells were relatively resistant to rapamycin even with suppressed activity of mTOR complex 1. Growth of T-ALL cells induced by Notch1 was profoundly affected by torin partially due to increased expression of Bcl2l11 and Bbc3. Of note, activation of Akt or knockdown of FoxO1 mitigated the effect of mTOR inhibition on T-ALL cells. Our data provide insight on the effect of mTOR inhibitors on the survival and proliferation of leukemic cells, thus further improving our understanding on cell-context-dependent impacts of mTOR signaling. [BMB Reports 2016; 49(1): 63-68]