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

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.