The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Key Laboratory of Famous Doctors' Proved Recipe Evaluation and Transformation Under State Administration of Traditional Chinese Medicine, Jiangsu Provincial Laboratory of Proved Anticarcinoma Recipe Research and Industrialization Engineering, Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Biomed Pharmacother. 2018 May;101:107-114. doi: 10.1016/j.biopha.2018.02.062. Epub 2018 Feb 23.
Colon cancer is the third most frequently diagnosed malignancy and has high morbidity worldwide. Epithelial-mesenchymal transition (EMT) has been increasingly implicated in colon cancer progression and metastasis. The present study was aimed to evaluate the potential antitumor activity of α-hederin, a monodesmosidic triterpenoid saponin isolated from Hedera helix, in human SW620 colon cancer cells stimulated with interleukin 6 (IL-6) for mimicking the tumor inflammatory microenvironment in vivo. Cell viability assay showed that IL-6 at 6.25 ng/ml significantly enhanced viability of SW620 cells, and thus this concentration was used to stimulate SW620 cells throughout this study. We observed that α-hederin concentration-dependently inhibited cell viability, migration and invasion in IL-6-treated SW620 cells. Moreover, α-hederin significantly restored IL-6-induced decrease in E-cadherin expression and abolished IL-6-induced increase in N-cadherin, vimentin, fibronectin, twist and snail at both mRNA and protein levels in SW620 cells. These data suggested that α-hederin suppressed IL-6-indcued EMT in colon cancer cells. Further molecular examinations showed that α-hederin inhibited phosphorylation of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3(STAT3), and halted the nuclear translocation of phosphorylated STAT3 in IL-6-treated SW620 cells. In addition, JAK2/STAT3 signaling inhibitor AG490 not only produced similar inhibitory effects on EMT markers as α-hederin, but also synergistically enhanced α-hederin's inhibitory effects on EMT markers in IL-6-treated SW620 cells. Altogether, we demonstrated that α-hederin suppressed IL-6-induced EMT associated with disruption of JAK2/STAT3 signaling in colon cancer cells. Our data strongly suggested α-hederin as a promising candidate for intervention of colon cancer and metastasis.
结肠癌是全球第三大常见恶性肿瘤，发病率较高。上皮-间充质转化（EMT）越来越多地被认为与结肠癌的进展和转移有关。本研究旨在评估从常春藤中分离得到的单糖苷三萜皂苷α-常春藤苷在模拟体内肿瘤炎症微环境的情况下，对人 SW620 结肠癌细胞中白细胞介素 6（IL-6）刺激的潜在抗肿瘤活性。细胞活力测定表明，6.25ng/ml 的 IL-6 显著增强了 SW620 细胞的活力，因此在整个研究过程中使用该浓度来刺激 SW620 细胞。我们观察到，α-常春藤苷浓度依赖性地抑制了 IL-6 处理的 SW620 细胞的活力、迁移和侵袭。此外，α-常春藤苷显著恢复了 IL-6 诱导的 SW620 细胞中 E-钙黏蛋白表达的降低，并消除了 IL-6 诱导的 N-钙黏蛋白、波形蛋白、纤连蛋白、twist 和 snail 在 mRNA 和蛋白水平的增加。这些数据表明，α-常春藤苷抑制了结肠癌细胞中 IL-6 诱导的 EMT。进一步的分子研究表明，α-常春藤苷抑制了 Janus 激酶 2（JAK2）和信号转导和转录激活因子 3（STAT3）的磷酸化，并阻止了磷酸化 STAT3 在 IL-6 处理的 SW620 细胞中的核转位。此外，JAK2/STAT3 信号抑制剂 AG490 不仅对 EMT 标志物产生了类似于 α-常春藤苷的抑制作用，而且还协同增强了 α-常春藤苷对 IL-6 处理的 SW620 细胞中 EMT 标志物的抑制作用。总之，我们证明了 α-常春藤苷抑制了 IL-6 诱导的 EMT，同时破坏了结肠癌细胞中的 JAK2/STAT3 信号。我们的数据强烈表明，α-常春藤苷是干预结肠癌和转移的有前途的候选药物。
