4-O-Methyihonokiol Protects HaCaT Cells from TGF-β1-Induced Cell Cycle Arrest by Regulating Canonical and Non-Canonical Pathways of TGF-β Signaling

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-beta (TGF-beta) signal pathway has an essential role in the regression induction of hair growth, the effect of 4-O-methylhonokiol on the TGF-beta signal pathway has not yet been elucidated. We thus examined the effect of 4-0-methylhonokiol on TGF-beta-induced canonical and noncanonical pathways in HaCaT human keratinocytes. When HaCaT cells were pretreated with 4-O-methylhonokiol, TGF-beta 1-induced G1/G0 phase arrest and TGF-beta 1-induced p21 expression were decreased. Moreover, 4-O-methylhonokiol inhibited nuclear translocation of Smad2/3, Smad4 and Sp1 in TGF-beta 1-induced canonical pathway. We observed that ERK phosphorylation by TGF-beta 1 was significantly attenuated by treatment with 4-O-methylhonokiol. 4-0-methylhonokiol inhibited TGF-beta 1-induced reactive oxygen species (ROS) production and reduced the increase of NADPH oxidase 4 (NOX4) mRNA level in TGF-beta 1-induced noncanonical pathway. These results indicate that 4-O-methylhonokiol could inhibit TGF-beta 1-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-beta 1-induced cell cycle arrest.