Niclosamide reverses adipocyte induced epithelial-mesenchymal transition in breast cancer cells via suppression of the interleukin-6/STAT3 signalling axis

Jones Gyamfi,Byung Soh Min,Junjeong Choi,Yun-Hee Lee

doi:10.1038/s41598-019-47707-2

Jones Gyamfi, Byung Soh Min + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-47707-2

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Journal: Scientific Reports	Publication Date: Aug 5, 2019
Citations: 41	License type: open-access

Affiliation: Yonsei University, Seoul National University

Abstract

The microenvironment of breast cancer comprises predominantly of adipocytes. Adipocytes drive cancer progression through the secretion adipocytokines. Adipocytes induce epithelial mesenchymal transition of breast cancer cells through paracrine IL-6/Stat3 signalling. Treatment approaches that can target adipocytes in the microenvironment and abrogate paracrine signals that drive breast cancer growth and metastasis are urgently needed. Repositioning of old drugs has become an effective approach for discovering new cancer drugs. In this study, niclosamide, an FDA approved anthelminthic drug was evaluated for its anti-breast cancer activity and its ability to inhibit adipocytes induced EMT. Niclosamide potently inhibited proliferation, migration and invasion at low concentration and induced significant apoptosis at high concentrations in human breast cancer cell lines MDA-MB-468 and MCF-7. Additionally, niclosamide reversed adipocyte-induced EMT with a correlated inhibition of IL-6/Stat3 activation and downregulation of EMT-TFs TWIST and SNAIL. Moreover, niclosamide markedly impaired MDA-MB-468 and MCF-7 migration and invasion. We further found that the inhibitory effects of niclosamide on MDA-MB-468 and MCF-7 motility was closely related to destabilization of focal adhesion complex formation. With decreased co-localization of focal adhesion kinase (FAK) and phosphorylated paxillin (pPAX). Collectively, these results demonstrate that niclosamide could be used to inhibit adipocyte-induced breast cancer growth and metastasis.

Highlights

The tumour microenvironment comprises proliferating tumour cells, the tumour stroma, infiltrating inflammatory cells and a variety of cancer associated cells[1,2]
Using stable signal transducer and activator of transcription 3 (STAT3) reporter cells, we showed that niclosamide significantly reduced STAT3 activity in both cells and inhibit breast cancer cell motility by destabilizing focal adhesion complex formation
Our results show that adipocyte is capable of activating STAT3 in breast cancer cells evidenced by increased expression of phosphorylated STAT3

Summary

Introduction

The tumour microenvironment comprises proliferating tumour cells, the tumour stroma, infiltrating inflammatory cells and a variety of cancer associated cells[1,2]. Adiponectin, autotaxin, interleukin 6 (IL-6), and transforming growth factor-β (TGF-β) have all been identified to be secreted by cancer-associated adipocytes[10]. These factors independently play diverse roles in tumour progression. We have previously reported human adipocytes induce EMT in MDA-MB-468 and MCF-7 breast cancer cells through paracrine IL-6 activation of STAT3, enhancing breast cancer cell migration and invasion, by induction of EMT19. We selected niclosamide based on available evidence of it potential to inhibit STAT3 phosphorylation and nuclear localization and systematically investigated its effects on adipocytes-induced EMT in MDA-MB-468 and MCF-7 breast cancer cells. Using stable STAT3 reporter cells, we showed that niclosamide significantly reduced STAT3 activity in both cells and inhibit breast cancer cell motility by destabilizing focal adhesion complex formation

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