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

Abstract

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-1α (HIF-1α) 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-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.

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-1α-targeted inhibition.

• Authors: Qi Su, Jingjing Wang, Qing Wu, Asmat Ullah, Mohsin Ahmad Ghauri, Ammar Sarwar, Li Chen, Feng Liu, Yanmin Zhang
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 84 Pg. 153503 (Apr 2021) ISSN: 1618-095X [Electronic] Germany
• PMID: 33636580 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier GmbH. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzophenanthridines
• EPHB4 protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Isoquinolines
• STAT3 Transcription Factor
• STAT3 protein, human
• sanguinarine
• Receptor, EphB4

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Benzophenanthridines (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Isoquinolines (pharmacology)
• Mice, Inbred BALB C
• Receptor, EphB4 (genetics, metabolism)
• STAT3 Transcription Factor (metabolism)
• Tumor Hypoxia (drug effects)
• Xenograft Model Antitumor Assays