title: Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-β-catenin signaling axis in a microRNA-34a dependent manner.
abstract: Obesity greatly influences risk, progression and prognosis of breast cancer. As molecular effects of obesity are largely mediated by adipocytokine leptin, finding effective novel strategies to antagonize neoplastic effects of leptin is desirable to disrupt obesity-cancer axis. Present study is designed to test the efficacy of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, against oncogenic actions of leptin and systematically elucidate the underlying mechanisms. Our results show that HNK significantly inhibits leptin-induced breast-cancer cell-growth, invasion, migration and leptin-induced breast-tumor-xenograft growth. Using a phospho-kinase screening array, we discover that HNK inhibits phosphorylation and activation of key molecules of leptin-signaling-network. Specifically, HNK inhibits leptin-induced Wnt1-MTA1-β-catenin signaling in vitro and in vivo. Finally, an integral role of miR-34a in HNK-mediated inhibition of Wnt1-MTA1-β-catenin axis was discovered. HNK inhibits Stat3 phosphorylation, abrogates its recruitment to miR-34a promoter and this release of repressor-Stat3 results in miR-34a activation leading to Wnt1-MTA1-β-catenin inhibition. Accordingly, HNK treatment inhibited breast tumor growth in diet-induced-obese mouse model (exhibiting high leptin levels) in a manner associated with activation of miR-34a and inhibition of MTA1-β-catenin. These data provide first in vitro and in vivo evidence for the leptin-antagonist potential of HNK revealing a crosstalk between HNK and miR34a and Wnt1-MTA1-β-catenin axis.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Dimiter B
authors.initials: DB
authors.lastname: Avtanski
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Nagalingam
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Panjamurthy
authors.initials: P
authors.lastname: Kuppusamy
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Bonner
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA.|Atlanta Veterans Administration Medical Center, Atlanta, GA, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Saxena
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Dipali
authors.initials: D
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use; D005260:Female; D006655:Histone Deacetylases; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D017705:Lignans / Q000627:therapeutic use*; D061986:MCF-7 Cells; D031566:Magnolia / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009765:Obesity / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors*; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D019938:Cyclin D1; D004365:Drugs, Chinese Herbal; D006655:Histone Deacetylases; D020738:Leptin; D017705:Lignans; D035683:MicroRNAs; D010936:Plant Extracts; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D051155:Wnt1 Protein; D051176:beta Catenin; C530104:CCND1 protein, human; C522425:MIRN34 microRNA, human; C089320:MTA1 protein, human; C494086:STAT3 protein, human; C495247:WNT1 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: breast cancer; honokiol; leptin; miR-34a