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Author Notes:

Correspondence to: Dipali Sharma, e-mail: dsharma7@jhmi.edu; Neeraj Saxena, e-mail: nsaxena@medicine.umaryland.edu

D.B. Avtanski and A. Nagalingam have contributed equally to this work.

Conflicts of Interest: None.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • Honokiol
  • leptin
  • LKB1
  • miR-34a
  • breast cancer
  • EPITHELIAL-MESENCHYMAL TRANSITION
  • LKB1 TUMOR-SUPPRESSOR
  • RECEPTOR OB-R
  • STEM-CELLS
  • CARCINOMA CELLS
  • PROTEIN-KINASE
  • IN-VIVO
  • GROWTH
  • EXPRESSION
  • OBESITY

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

Tools:

Journal Title:

Oncotarget

Volume:

Volume 6, Number 30

Publisher:

, Pages 29947-29962

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015 Avtanski et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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