Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis

• Type of Material: Article
• Authors: Dimiter B. Autanski, Johns Hopkins University; Arumugam Nagalingam, Johns Hopkins University; Michael Y. Bonner, Emory University; Jack Arbiser, Emory University; Neeraj K. Saxena, University of Maryland; Dipali Sharma, Johns Hopkins University
• Language: English
• Date: 2014-05-01
• Publisher: Wiley Open Access
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Federation of European Biochemical Societies.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molonc.2014.01.004
• Title of Journal or Parent Work: Molecular Oncology
• ISSN: 1574-7891
• Volume: 8
• Issue: 3
• Start Page: 565
• End Page: 580
• Grant/Funding Information: This work was supported by NIDDK NIH, K01DK076742 and R03DK089130 (to NKS); NCI NIH R01AR47901 (to JLA); NCI NIH R01CA131294; Safeway Foundation; Avon Foundation; Breast Cancer Research Foundation (BCRF) 90047965 (to DS).
• Keywords: Science & Technology; NATURAL-PRODUCT; HEPATOCELLULAR-CARCINOMA; Honokiol; NF-KAPPA-B; E-CADHERIN EXPRESSION; IN-VITRO; EMT; Zeb1; STEM-CELLS; MOLECULAR TARGETS; Stat3; Oncology; ONCOGENIC ACTIONS; DOWN-REGULATION; MAGNOLIA-OFFICINALIS; E-cadherin; Breast cancer; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry; Health Sciences, Medicine and Surgery

Abstract

Epithelial-mesenchymal transition (EMT), a critical step in the acquisition of metastatic state, is an attractive target for therapeutic interventions directed against tumor metastasis. Honokiol (HNK) is a natural phenolic compound isolated from an extract of seed cones from Magnolia grandiflora. Recent studies from our lab show that HNK impedes breast carcinogenesis. Here, we provide molecular evidence that HNK inhibits EMT in breast cancer cells resulting in significant downregulation of mesenchymal marker proteins and concurrent upregulation of epithelial markers. Experimental EMT induced by exposure to TGFβ and TNFα in spontaneously immortalized nontumorigenic human mammary epithelial cells is also completely reversed by HNK as evidenced by morphological as well as molecular changes. Investigating the downstream mediator(s) that may direct EMT inhibition by HNK, we found functional interactions between HNK, Stat3, and EMT-signaling components. Invitro and invivo analyses show that HNK inhibits Stat3 activation in breast cancer cells and tumors. Constitutive activation of Stat3 abrogates HNK-mediated activation of epithelial markers whereas inhibition of Stat3 using small molecule inhibitor, Stattic, potentiates HNK-mediated inhibition of EMT markers, invasion and migration of breast cancer cells. Mechanistically, HNK inhibits recruitment of Stat3 on mesenchymal transcription factor Zeb1 promoter resulting in decreased Zeb1 expression and nuclear translocation. We also discover that HNK increases E-cadherin expression via Stat3-mediated release of Zeb1 from E-cadherin promoter. Collectively, this study reports that HNK effectively inhibits EMT in breast cancer cells and provide evidence for a previously unrecognized cross-talk between HNK and Stat3/Zeb1/E-cadherin axis.