The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2-STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells.
The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2-STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells.
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姜黄素类似物 2-吡啶基环己酮通过抑制人食管鳞状细胞癌细胞中的 JAK2-STAT3 途径诱导细胞凋亡。
DOI：
10.3389/fphar.2018.00820
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发表时间：
2018
影响因子：
5.6
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Wang Y;Zhou P;Qin S;Xu D;Liu Y;Fu W;Ruan B;Zhang L;Zhang Y;Wang X;Pan Y;Wang S;Yan H;Qin J;Wang X;Liu Q;Du Z;Liu Z;Wang Y
已经研究了对姜黄素结构的多种修饰，目的是提高其效力和生化性质。在此之前，我们已经合成了一系列姜黄素类似物。本研究探讨了姜黄素类似物2-吡啶基环己酮对食管癌Eca 109和EC 9706细胞的抗肿瘤作用及其分子机制。2-吡啶基环己酮抑制Eca 109和EC 9706细胞的增殖，诱导细胞凋亡的形态学变化，膜磷脂酰丝氨酸外翻，半胱氨酸蛋白酶3激活，和裂解的聚（ADP-核糖）聚合酶。机制研究表明，2-吡啶基环己酮破坏线粒体膜电位，扰乱Bcl-2家族蛋白的平衡，并通过线粒体介导的内源性途径引发细胞凋亡。在2-吡啶环己酮处理的细胞中，JAK 2和STAT 3的磷酸化水平呈剂量依赖性降低，p38和p-ERK信号以剂量依赖性方式显著激活。此外，我们发现，添加STAT 3抑制剂S3 I-201，导致Eca 109细胞中Bcl-2的表达水平降低。染色质免疫沉淀实验表明，在Eca 109细胞中STAT 3与Bcl-2的启动子结合。此外，单独Bcl-2基因启动子上的四个STAT 3结合位点（−1733/−1723、−1627/−1617、−807/−797和−134/−124）的突变减弱了STAT 3的转录激活。此外，下调STAT 3表达可降低STAT 3对Bcl-2表达的转录活性。这些数据提供了一个潜在的分子机制的凋亡诱导功能的2-吡啶基环己酮，并强调其作为一种治疗剂的食管鳞癌的重要作用。
Multiple modifications to the structure of curcumin have been investigated with an aim to improve its potency and biochemical properties. Previously, we have synthesized a series of curcumin analogs. In the present study, the anticancer effect of 2-pyridyl cyclohexanone, one of the curcumin analogs, on esophageal carcinoma Eca109 and EC9706 cell lines and its molecular mechanisms were investigated. 2-Pyridyl cyclohexanone inhibited the proliferation of Eca109 and EC9706 cells by inducing apoptosis as indicated by morphological changes, membrane phospholipid phosphatidylserine ectropion, caspase 3 activation, and cleavage of poly(ADP-ribose) polymerase. Mechanistic studies indicated that 2-pyridyl cyclohexanone disrupted mitochondrial membrane potential, disturbed the balance of the Bcl-2 family proteins, and triggered apoptosis via the mitochondria-mediated intrinsic pathway. In 2-pyridine cyclohexanone-treated cells, the phosphorylation levels of JAK2 and STAT3 were dose-dependently decreased and p38 and p-ERK signals were notably activated in a dose-dependent manner. Moreover, we found that the addition of S3I-201, a STAT3 inhibitor, led to a decreased expression level of Bcl-2 in Eca109 cells. The chromatin immunoprecipitation assay demonstrated that STAT3 bound to the promoter of Bcl-2 in the Eca109 cells. Furthermore, the mutation of four STAT3 binding sites (−1733/−1723, −1627/−1617, −807/−797, and −134/−124) on the promote of Bcl-2 gene alone attenuated the transcriptional activation of STAT3. In addition, down-regulation of STAT3 resulted in less of transcriptional activity of STAT3 on Bcl-2 expression. These data provide a potential molecular mechanism of the apoptotic induction function of 2-pyridyl cyclohexanone, and emphasize its important roles as a therapeutic agent for esophageal squamous carcinoma.
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影响因子：
8
作者：
Garg N;Bakhshinyan D;Venugopal C;Mahendram S;Rosa DA;Vijayakumar T;Manoranjan B;Hallett R;McFarlane N;Delaney KH;Kwiecien JM;Arpin CC;Lai PS;Gómez-Biagi RF;Ali AM;de Araujo ED;Ajani OA;Hassell JA;Gunning PT;Singh SK
通讯作者：
Singh SK
影响因子：
4.3
作者：
Cui, Yuting;Lu, Peiran;Liu, Xuebo
通讯作者：
Liu, Xuebo
影响因子：
6.4
作者：
Chakravarti, Nitin;Myers, Jeffrey N.;Aggarwal, Bharat B.
通讯作者：
Aggarwal, Bharat B.
影响因子：
5.8
作者：
Blasius, Romain;Reuter, Simone;Diederich, Marc
通讯作者：
Diederich, Marc
影响因子：
2.7
作者：
Fuchs, James R.;Pandit, Bulbul;Li, Pui-Kai
通讯作者：
Li, Pui-Kai