title: Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer.
abstract: Leptin, a major adipocytokine produced by adipocytes, is emerging as a key molecule linking obesity with breast cancer therefore, it is important to find effective strategies to antagonize oncogenic effects of leptin to disrupt obesity-cancer axis. Here, we examine the potential of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, as a leptin-antagonist and systematically elucidate the underlying mechanisms. HNK inhibits leptin-induced epithelial-mesenchymal-transition (EMT), and mammosphere-formation along with a reduction in the expression of stemness factors, Oct4 and Nanog. Investigating the downstream mediator(s), that direct leptin-antagonist actions of HNK; we discovered functional interactions between HNK, LKB1 and miR-34a. HNK increases the expression and cytoplasmic-localization of LKB1 while HNK-induced SIRT1/3 accentuates the cytoplasmic-localization of LKB1. We found that HNK increases miR-34a in LKB1-dependent manner as LKB1-silencing impedes HNK-induced miR-34a which can be rescued by LKB1-overexpression. Finally, an integral role of miR-34a is discovered as miR-34a mimic potentiates HNK-mediated inhibition of EMT, Zeb1 expression and nuclear-localization, mammosphere-formation, and expression of stemness factors. Leptin-antagonist actions of HNK are further enhanced by miR-34a mimic whereas miR-34a inhibitor results in inhibiting HNK's effect on leptin. These data provide evidence for the leptin-antagonist potential of HNK and reveal the involvement of LKB1 and miR-34a.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, 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 21231, USA.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Nagalingam
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA 30322, 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 30322, USA.|Atlanta Veterans Administration Medical Center, Atlanta, GA 30322, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, 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 21231, USA.
authors.forename: Dipali
authors.initials: D
authors.lastname: Sharma
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D017705:Lignans / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D018613:Microscopy, Confocal; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D019938:Cyclin D1; D020738:Leptin; D017705:Lignans; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; C522425:MIRN34 microRNA, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C109790:STK11 protein, human
keywords: Honokiol; LKB1; breast cancer; leptin; miR-34a