Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells.
Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells.
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DOI：
10.1155/2017/5958429
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发表时间：
2017
影响因子：
4.6
通讯作者：
Vadgama JV
中科院分区：
文献类型：
--
作者：
Chung SS;Wu Y;Okobi Q;Adekoya D;Atefi M;Clarke O;Dutta P;Vadgama JV
越来越多的证据表明促炎细胞因子参与癌症的发展。在这里，我们发现两种细胞因子，IL-6 和 TNF-α，激活结直肠癌细胞更具侵袭性和干细胞样。 IL-6和TNF-α以协同方式联合治疗磷酸化转录因子STAT3。 STAT3、STAT1 和 NF-κB 在细胞因子刺激后发生物理相互作用。 STAT3 与人端粒酶逆转录酶 (hTERT) 的启动子区域结合。 IL-6 和 TNF-α 刺激进一步增强了 STAT3 结合亲和力。 IL-6 和 TNF-α 刺激后，结直肠癌细胞中干细胞标记物 Oct-4 上调。 Withaferin A 是一种抗炎类固醇内酯，可抑制 IL-6 和 TNF-α 诱导的癌细胞侵袭并减少结肠球形成。值得注意的是，醉茄素 A 抑制 STAT3 磷酸化并消除 STAT3、STAT1 和 NF-κB 相互作用。 Oct-4 表达也因醉茄素 A 抑制而下调。 STAT3 与 hTERT 启动子区域的结合和端粒酶活性显示，醉茄素 A 处理会降低。促炎细胞因子诱导的癌细胞侵袭性是由结直肠癌细胞中的 STAT3 调节机制介导的。我们的数据表明，醉茄素 A 可能是一种有前途的抗癌药物，可以有效抑制结直肠癌的进展。
There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-κB physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT). IL-6 and TNF-α stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-α stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-α-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-κB interactions. Oct-4 expression was also downregulated by withaferin A inhibition. The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments. Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells. Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer.