Biomolecules & Therapeutics  
4-O-Methylhonokiol Protects HaCaT Cells from TGF-β1-Induced Cell Cycle Arrest by Regulating of Canonical and Non-Canonical Pathways of TGF-β Signaling
Sang-Cheol Kim1,3 Jung-Il Kang1, Jin-Won Hyun1, Ji-Hoon Kang1, Young-Sang Koh1, Young-Heui Kim2, Ki-Ho Kim2, Ji-Hee Ko1, Eun-Sook Yoo1 and Hee-Kyoung Kang1,*
1Department of Medicine, Jeju National University School of Medicine, Jeju 63243, 2R&D Center, Bioland Ltd., Cheonan 31257, 3Freshwater Bioresources Utilization Division, Nakdonggang National Institute of Biological Resourecs, Sangju 37242, Republic of Korea
E-mail: pharmkhk@jejunu.ac.kr
Tel: +82-64-754-3846, Fax: +82-64-702-2687
Received: January 6, 2016; Revised: October 7, 2016; Accepted: November 15, 2016; Published online: February 13, 2017.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
4-O-methylhonokiol, a neolignan compound from Magnolia Officinalis, has been reported to have various biological activities including hair growth promoting effect. However, although transforming growth factor-β (TGF-β) signal pathway has an essential role in the regression induction of hair growth, the effect of 4-O-methylhonokiol on the TGF-β signal pathwayhas not yet been elucidated. We thus examined the effect of 4-O-methylhonokiol on TGF-β-induced canonical and noncanonical pathways in HaCaT human keratinocytes. When HaCaT cells were pretreated with 4-O-methylhonokiol, TGF-β1-induced G1/G0 phase arrest and TGF- β1-induced p21 expression were decreased. Moreover, 4-O-methylhonokiol inhibited nuclear translocation of Smad2/3, Smad4 and Sp1 in TGF-β1-induced canonical pathway. We observed that ERK phosphorylation by TGF-β1 was significantly attenuated by treatment with 4-O-methylhonokiol. 4-O-methylhonokiol inhibited TGF-β1-induced reactive oxygen species (ROS) production and reduced the increase of NADPH oxidase 4 (NOX4) mRNA level in TGF-β1-induced noncanonical pathway. These results indicate that 4-O-methylhonokiol could inhibit TGF-β1-induced cell cycle arrest through inhibition of canonical and noncanonical pathways in human keratinocyte HaCaT cell and that 4-O-methylhonokiol might have protective action on TGF-β1-induced cell cycle arrest.
Keywords: 4-O-methylhonokiol, Transforming growth factor-β1, Cell cycle arrest, Smads, Reactive oxygen species, NADPH oxidase 4


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