Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1α pathways in breast cancer

Background: 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. Purpose: We explore the effect of sanguinarine on hypoxia-induced activation of Ephrin type-B receptor 4 (EphB4) and hypoxia inducible factor-1 alpha (HIF-1 alpha) pathways in breast cancer. Results: 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-1 alpha expression. Sanguinarine inhibited the activation of downstream protein signal transducer and activator of transcription-3 (STAT3), thereby blocking hypoxia-induced HIF-1 alpha/STAT3 interaction and downregulating the mRNA levels of their target genes. Mechanically, sanguinarine attenuated HIF-1 alpha protein levels via inhibition of MAPK/ERK pathways and promotion of HIF-1 alpha 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. Conclusions: Our results may bring insights to the hypoxia-induced pathways in breast cancers, and suggest sanguinarine as a promising candidate for EphB4 and HIF-1 alpha-targeted inhibition.