title: Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis.
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. In vitro and in vivo 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.
authors: Department of Oncology, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors: Dimiter B
authors: DB
authors: Avtanski
authors: Department of Oncology, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors: Arumugam
authors: A
authors: Nagalingam
authors: Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322, USA.
authors: Michael Y
authors: MY
authors: Bonner
authors: Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA 30322, USA.
authors: Jack L
authors: JL
authors: Arbiser
authors: Department of Medicine, University of Maryland School of Medicine, 660 W Redwood St., Howard Hall, Rm 301, Baltimore, MD 21201, USA. Electronic address: nsaxena@medicine.umaryland.edu.
authors: Neeraj K
authors: NK
authors: Saxena
authors: Department of Oncology, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. Electronic address: dsharma7@jhmi.edu.
authors: Dipali
authors: D
authors: Sharma
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D015820:Cadherins; D018398:Homeodomain Proteins; D017705:Lignans; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C486307:ZEB1 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Breast cancer; E-cadherin; EMT; Honokiol; Stat3; Zeb1