Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer
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Dimiter B. Avtanski1,*, Arumugam Nagalingam1,*, Michael Y. Bonner3, Jack L. Arbiser3,4, Neeraj K. Saxena2, Dipali Sharma1
1Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD 21231
2Department of Medicine, University of Maryland School of Medicine, Baltimore MD 21201
3Department of Dermatology, Emory University School of Medicine, Winship Cancer Institute
4Atlanta Veterans Administration Medical Center, Atlanta, GA 30322
*These authors have contributed equally to this work
Dipali Sharma, e-mail: [email protected]
Neeraj Saxena, e-mail: [email protected]
Keywords: Honokiol, leptin, LKB1, miR-34a, breast cancer
Received: May 13, 2015 Accepted: August 13, 2015 Published: August 24, 2015
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.
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