Chung Seyung S, Wu Yong, Okobi Quincy, Adekoya Debbie, Atefi Mohammad, Clarke Orette, Dutta Pranabananda, Vadgama Jaydutt V
Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USA.
Charles R. Drew University of Medicine and Science, 1731 East 120th street, Los Angeles, CA 90059, USA.
Mediators Inflamm. 2017;2017:5958429. doi: 10.1155/2017/5958429. Epub 2017 Jun 6.
There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF- phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-B physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT). IL-6 and TNF- stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF- stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF--induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-B 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.
越来越多的证据表明促炎细胞因子参与癌症发展。在此，我们发现两种细胞因子，即白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α），可激活结肠癌细胞，使其更具侵袭性且更具干细胞样特性。IL-6和TNF-α联合处理以协同方式使转录因子信号转导和转录激活因子3（STAT3）磷酸化。在细胞因子刺激下，STAT3、信号转导和转录激活因子1（STAT1）以及核因子κB（NF-κB）发生物理相互作用。STAT3与人类端粒酶逆转录酶（hTERT）的启动子区域结合。IL-6和TNF-α刺激进一步增强了STAT3的结合亲和力。在IL-6和TNF-α刺激后，结肠癌细胞中的干细胞标志物八聚体结合转录因子4（Oct-4）上调。抗炎甾体内酯Withaferin A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，Withaferin A抑制STAT3磷酸化，并消除了STAT3、STAT1和NF-κB的相互作用。Withaferin A抑制也下调了Oct-4表达。Withaferin A处理后，STAT3与hTERT启动子区域的结合以及端粒酶活性降低。促炎细胞因子诱导的癌细胞侵袭是由结肠癌细胞中STAT3调节的机制介导的。我们的数据表明，Withaferin A可能是一种有前景的抗癌药物，可有效抑制结肠癌的进展。
