Paeonol inhibits B16F10 melanoma metastasis In vitro and In Vivo via disrupting proinflammatory cytokines‐mediated NF‐κB and STAT3 pathways
Paeonol inhibits B16F10 melanoma metastasis In vitro and In Vivo via disrupting proinflammatory cytokines‐mediated NF‐κB and STAT3 pathways
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DOI：
10.1002/iub.1435
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发表时间：
2015-10
期刊：
影响因子：
4.6
通讯作者：
Lei Zhang;L. Tao;TianLu Shi;Feng Zhang;Xiaobo Sheng;Yuzhu Cao;Shizhong Zheng;Aiyun Wang;Wenhui Qian;Ling Jiang;Yin Lu
中科院分区：
文献类型：
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作者：
Lei Zhang;L. Tao;TianLu Shi;Feng Zhang;Xiaobo Sheng;Yuzhu Cao;Shizhong Zheng;Aiyun Wang;Wenhui Qian;Ling Jiang;Yin Lu
癌症相关炎症（CRI）现在被认为是许多类型恶性肿瘤发病机制的第七个标志。丹皮酚是一种从牡丹根皮中分离得到的天然酚类成分，具有显著的抗炎活性。近年来，越来越多的研究发现丹皮酚具有很强的抗肿瘤作用。然而，基于CRI对其抗癌机制知之甚少。在本研究中，我们观察到丹皮酚通过抑制细胞增殖、诱导细胞凋亡发挥直接的抗癌活性，并通过减少B16F10小鼠黑色素瘤细胞条件培养基中促炎细胞因子（TNF‐α、IL‐1β、IL‐6和TGF‐β）的分泌发挥明显的抗炎作用。有趣的是，我们发现丹皮酚显著逆转TNF - α -或IL - 6 -诱导的B16F10单细胞和体外集体迁移和侵袭的运动表型，这与影响上皮-间充质转化（EMT）的制造和MMPs的表达有关。特别是，丹皮酚破坏了B16F10细胞中TNF - α激活的NF - κB和IL - 6激活的STAT3信号通路。EMSA和荧光素酶检测显示，在TNF - α存在的情况下，丹皮酚可以抑制NF - κB结合和NF - κB驱动的启动子活性。最后，我们发现丹皮酚可以降低血清促炎细胞因子水平下调的C57/BL6J小鼠的B16F10自发性肺转移。因此，丹皮酚通过阻断促炎细胞因子介导的NF - κB和STAT3信号激活的侵袭性反馈，在黑色素瘤细胞和小鼠模型中具有抗肿瘤活性。这些发现提供了一种新的治疗策略，丹皮酚可能是一种有希望的癌症相关炎症的多功能辅助治疗。©2015 IUBMB生活，67(10):778-788,2015
Cancer related inflammation (CRI) is now recognized as the seventh hallmark in the pathogenesis of many types of malignancies. Paeonol, a natural phenolic component isolated from the root bark of Paeonia moutan, has significant anti‐inflammatory activity. Recently, accumulating body of research has revealed potent anti‐tumor effects mediated by paeonol. However, little is known about its anticancer mechanism on the basis of CRI. In this study, we observed that paeonol exerted direct anticancer activity through inhibition of cell proliferation, induction of apoptosis, and evident anti‐inflammatory effects by reducing proinflammatory cytokines secretion (TNF‐α, IL‐1β, IL‐6, and TGF‐β) in the conditioned medium of B16F10 mouse melanoma cells. Interestingly, we found that paeonol significantly reversed motility phenotypes in TNF‐α‐ or IL‐6‐induced B16F10 singe cell and collective migration and invasion in vitro, which were related to affecting epithelial‐to‐mesenchymal transition (EMT) makers and MMPs expression. In particular, paeonol disrupted both TNF‐α‐activated NF‐κB and IL‐6‐activated STAT3 signaling pathways in B16F10 cells. EMSA and luciferase assays showed that paeonol abrogated NF‐κB binding and NF‐κB‐driven promoter activity in the presence of TNF‐α. Finally, we showed that paeonol attenuated B16F10 spontaneous lung metastases in C57/BL6J mice with down‐regulated levels of serum proinflammatory cytokines. Therefore, paeonol possessed antitumor activity in melanoma cells and mice model by interruption of the aggressive feedback through proinflammatory cytokines mediated NF‐κB and STAT3 signaling activation. These findings provide a novel treatment strategy that paeonol might be a promising versatile adjuvant therapy for cancer related inflammation. © 2015 IUBMB Life, 67(10):778–788, 2015