Sanguinarine disrupts the colocalization and interaction of HIF-1α with tyrosine and serine phosphorylated-STAT3 in breast cancer.

Qi Su,Dongdong Zhang,Asmat Ullah,Yanmin Zhang,Jingjing Wang,Mohsin Ahmad Ghauri,Bo Wang,Yingzhuan Zhan,Bingling Dai,Mengying Fan

doi:10.1111/jcmm.15056

Abstract

Breast cancer is one leading cause of death in females, especially triple‐negative breast cancer (TNBC). Hypoxia is a key feature leading to tumour progression driven by hypoxia‐inducible factor (HIF)‐1α. The aim is to investigate the mechanism of HIF‐1α and signal transducer and activator of transcription‐3 (STAT3) interaction and discover a compound to disrupt the interaction in breast cancer cells. The regulation pattern of HIF‐1α and STAT3 was analysed in hypoxic TNBC cells and patient samples. The effects of a natural alkaloid, sanguinarine, on HIF‐1α and STAT3 colocalization and interaction were evaluated in vitro and mouse xenograft models. We observed strong colocalization of HIF‐1α, p‐STAT3‐Tyr and p‐STAT3‐Ser in TNBC patient samples. Sanguinarine could inhibit the nuclear colocalization and interaction of HIF‐1α with p‐STAT3‐Tyr and p‐STAT3‐Ser in vivo and in vitro. Our results may bring insights to the HIF‐1α/STAT3 interaction in breast cancers and suggest sanguinarine as a promising candidate for HIF‐α/STAT3 inhibition.

Highlights

Breast cancer is the most diagnosed and the leading cause of cancer-related death in women globally.[1]
Reduced oxygen activity elevates the activity of hypoxia-inducible factor-1α (HIF-1α) which is degraded under normoxia
Recent studies revealed that hypoxia leads to the activation of phospho-signal transducer and activator of transcription-3 (STAT3)-Tyr, and STAT3 has been suggested to cooperate with HIF-1α in VEGF activation under hypoxia in cancer cells.[8]

Summary

| INTRODUCTION

Breast cancer is the most diagnosed and the leading cause of cancer-related death in women globally.[1]. As a transcription factor, stabilized HIF-1α forms heterodimers and translocates to the nucleus, thereby binding to HIF responsive elements and activating target genes,[5] indicating that targeting upstream HIF-1α and its cofactors could be a potential treatment option for TNBC. Recent studies revealed that hypoxia leads to the activation of phospho-STAT3-Tyr, and STAT3 has been suggested to cooperate with HIF-1α in VEGF activation under hypoxia in cancer cells.[8]. The discovery of small molecular compounds interfering with the cooperation of HIF-1α/ STAT3 may gain more insights to the clinical treatment for breast cancer. We found that in line with expression pattern in TNBC patient samples, hypoxia increased HIF-1α levels and STAT3 phosphorylation at tyrosine and serine residues in TNBC cells. Sanguinarine could effectively disrupt HIF-1α/STAT3 colocalization and interaction

| MATERIALS AND METHODS

Findings

| DISCUSSION