血桂碱
车站3
癌症研究
MAPK/ERK通路
信号转导
缺氧(环境)
生物
乳腺癌
药理学
癌症
化学
细胞生物学
生物碱
植物
有机化学
氧气
遗传学
作者
Qi Su,Jingjing Wang,Qing Wu,Asmat Ullah,Mohsin Ahmad Ghauri,Ammar Sarwar,Li Chen,Feng Liu,Yanmin Zhang
出处
期刊:Phytomedicine
[Elsevier]
日期:2021-04-01
卷期号:84: 153503-153503
被引量:28
标识
DOI:10.1016/j.phymed.2021.153503
摘要
Breast cancer is the most common female cancer worldwide. Large hypoxic area is one of the features of tumor microenvironment. Highly activated hypoxia-induced pathways positively correlate with poor clinical response to chemo- and radiotherapy and high mortality in breast cancer patients. We explore the effect of sanguinarine on hypoxia-induced activation of Ephrin type-B receptor 4 (EphB4) and hypoxia inducible factor-1α (HIF-1α) pathways in breast cancer. Hypoxia-induced expression of a receptor tyrosine kinase EphB4 was observed in hypoxic breast cancer cell models. Sanguinarine, a natural alkaloid, could effectively combat hypoxia-induced EphB4 and HIF-1α expression. Sanguinarine inhibited the activation of downstream protein signal transducer and activator of transcription-3 (STAT3), thereby blocking hypoxia-induced HIF-1α/STAT3 interaction and downregulating the mRNA levels of their target genes. Mechanically, sanguinarine attenuated HIF-1α protein levels via inhibition of MAPK/ERK pathways and promotion of HIF-1α proteasome degradation. Sanguinarine inhibited STAT3 activation through targeting its upstream EphB4 and accelerating STAT3 dephosphorylation. Correspondingly, xenograft models confirmed that sanguinarine treatment disrupted hypoxia-induced pathways and inhibited tumor growth in vivo. Our results may bring insights to the hypoxia-induced pathways in breast cancers, and suggest sanguinarine as a promising candidate for EphB4 and HIF-1α-targeted inhibition.
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