TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL-2R signalling pathway
TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL-2R signalling pathway
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TPD7通过调节IL-2R信号通路抑制皮肤T细胞淋巴瘤H9细胞生长
DOI：
10.1111/jcmm.14810
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发表时间：
2019
影响因子：
5.3
通讯作者：
Ma Weina
中科院分区：
文献类型：
--
作者：
Zhu Man;Yang Liu;Shi Xianpeng;Gong Zhengyan;Yu Runze;Zhang Dongdong;Zhang Yanmin;Ma Weina
IL-2 R通路是免疫细胞发育的关键调节因子，已成为癌症治疗中有前途的药物靶点，但相关抑制剂缺乏。TPD 7是一种新的联苯脲塔斯品碱衍生物，已显示出抗癌作用。在这里，我们证明了TPD 7在皮肤T细胞淋巴瘤中的抗癌活性，并研究了TPD 7通过IL-2 R信号传导的潜在机制。TPD 7对细胞活力的抑制作用与IL-2 R的表达水平密切相关，皮肤T细胞淋巴瘤H9和HUT 78细胞对TPD 7最敏感。TPD 7与IL-2 R很好地结合，并下调IL-2 R的mRNA和蛋白水平。TPD 7还可抑制IL-2 R下游的JAK/STAT、PI 3 K/AKT/mTOR和PLCγ/Raf/MAPK信号通路，从而调控Bcl-2线粒体凋亡途径和细胞周期蛋白CDK/Cyclins。流式细胞仪分析证实，TPD 7通过线粒体途径促进H9细胞凋亡，并使细胞周期阻滞于G2/M期。TPD 7是一种新型抗癌药物，可能通过调节IL-2 R信号通路而成为治疗皮肤T细胞淋巴瘤的潜在候选药物。
IL‐2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti‐cancer effect. Here, we demonstrated the anti‐cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL‐2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL‐2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL‐2R and down‐regulated the mRNA and protein levels of IL‐2R. Furthermore, TPD7 suppressed the downstream cascades of IL‐2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl‐2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti‐cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL‐2R signalling pathway.