鼻涕虫
下调和上调
上皮-间质转换
波形蛋白
化学
细胞凋亡
PI3K/AKT/mTOR通路
MAPK/ERK通路
细胞生长
癌细胞
细胞生物学
细胞迁移
癌症研究
细胞
信号转导
生物化学
癌症
生物
免疫学
免疫组织化学
基因
遗传学
作者
Jing Ying Wang,Zhe Wang,Ming Yue Li,Zhihong Zhang,Chunliu Mi,Hong Xiang Zuo,Yue Xing,Yan‐Ling Wu,Li‐Hua Lian,Guang Xu,Lian Xun Piao,Juan Ma,Xuejun Jin
标识
DOI:10.1016/j.cbi.2018.09.014
摘要
Dictamnine (DTM) is a natural alkaloid isolated from the root of Dictamnus dasycarpus Turcz and has been shown to exhibit multiple biological functions, including anti-inflammatory, antifungal, anti-angiogenic and anticancer activity. However, the mechanisms by which dictamnine inhibits tumor growth are not fully understood. In this study, we investigated the effectiveness of dictamnine as a treatment for cancer and to identify the underlying mechanisms of its anticancer activity. Here, dictamnine showed the potent inhibitory activity against HIF-1α and Slug activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α and Slug protein in a dose-dependent manner. Further analysis revealed that dictamnine inhibited HIF-1α protein synthesis, without affecting its degradation. Our results demonstrated that dictamnine reduced HIF-1α protein synthesis by downregulating the mTOR/p70S6K/eIF4E and MAPK pathways, and reduced the expression of Slug by inhibiting the GSK-3β/Slug signaling pathway. Moreover, epithelial-mesenchymal transition (EMT) was inhibited in dictamnine-treated tumors by downregulation of HIF-1α and Slug, as reflected by the upregulation of E-cadherin and Occludin, and the downregulation of N-cadherin and Vimentin. Phenomenological experiments showed that dictamnine reduced migration and invasion, inhibited HCT116 cell proliferation and promoted HCT116 cell apoptosis by downregulating HIF-1α and Slug. In vivo studies further confirmed that dictamnine treatment caused significant inhibition of tumor growth in a xenograft tumor model. These findings suggest that dictamnine is a potent cancer inhibitor, providing a rationale for anticancer pathway-targeted therapy.
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