Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer

• Type of Material: Article
• Authors: Dimiter B. Avtanski, 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: 2015-10-06
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Avtanski et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.4937
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 6
• Issue: 30
• Start Page: 29947
• End Page: 29962
• Grant/Funding Information: This work was supported by NCI NIH, 1R21CA185943-01 (to NKS); NCI NIH R01AR47901 (to JLA), NCI NIH R01CA131294, NCI NIH R21CA155686, Avon Foundation, Breast Cancer Research Foundation (BCRF) 90047965 (to DS).
• Keywords: PROTEIN-KINASE; leptin; LKB1 TUMOR-SUPPRESSOR; EPITHELIAL-MESENCHYMAL TRANSITION; Cell Biology; GROWTH; Life Sciences & Biomedicine; miR-34a; EXPRESSION; LKB1; Oncology; CARCINOMA CELLS; Honokiol; STEM-CELLS; breast cancer; RECEPTOR OB-R; OBESITY; IN-VIVO; Science & Technology
• Research Categories: Health Sciences, Oncology; Biology, Cell

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.