Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2019.206
Vanillic Acid Stimulates Anagen Signaling via the PI3K/Akt/β-Catenin Pathway in Dermal Papilla Cells
Jung-Il Kang1, Youn Kyung Choi1, Young-Sang Koh1,2, Jin-Won Hyun1,2, Ji-Hoon Kang1, Kwang Sik Lee3, Chun Mong Lee3, Eun-Sook Yoo1,2 and Hee-Kyoung Kang1,2,*
1Department of Medicine, School of Medicine, Jeju National University, Jeju 63243,
2Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243,
3Songpa R&D Center, Coreana Cosmetic Co., Ltd, Chenan 31041, Republic of Korea
*E-mail: pharmkhk@jejunu.ac.kr
Tel: +82-64-754-3846, Fax: +82-64-702-2687
Received: December 4, 2019; Revised: February 18, 2020; Accepted: March 23, 2020; Published online: May 12, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
The hair cycle (anagen, catagen, and telogen) is regulated by the interaction between mesenchymal cells and epithelial cells in the hair follicles. The proliferation of dermal papilla cells (DPCs), mesenchymal-derived fibroblasts, has emerged as a target for the regulation of the hair cycle. Here, we show that vanillic acid, a phenolic acid from wheat bran, promotes the proliferation of DPCs via a PI3K/Akt/Wnt/β-catenin dependent mechanism. Vanillic acid promoted the proliferation of DPCs, accompanied by increased levels of cell-cycle proteins cyclin D1, CDK6, and Cdc2 p34. Vanillic acid also increased the levels of phospho(ser473)-Akt, phospho(ser780)-pRB, and phospho(thr37/46)-4EBP1 in a time-dependent manner. Wortmannin, an inhibitor of the PI3K/Akt pathway, attenuated the vanillic acid-mediated proliferation of DPCs. Vanillic acid-induced progression of the cell-cycle was also suppressed by wortmannin. Moreover, vanillic acid increased the levels of Wnt/β-catenin proteins, such as phospho(ser9)-glycogen synthase kinase-3β (GSK-3β), phospho(ser552)-β-catenin, and phospho(ser675)-β-catenin. We found that vanillic acid increased the levels of cyclin D1 and Cox-2, which are target genes of β-catenin, and these changes were inhibited by wortmannin. To investigate whether vanillic acid affects the downregulation of β-catenin by dihydrotestosterone (DHT), implicated in the development of androgenetic alopecia, DPCs were stimulated with DHT in the presence and absence of vanillic acid for 24 h. Western blotting and confocal microscopy analyses showed that the decreased level of β-catenin after the incubation with DHT was reversed by vanillic acid. These results suggest that vanillic acid could stimulate anagen and alleviate hair loss by activating the PI3K/Akt and Wnt/β-catenin pathways in DPCs.
Keywords: Vanillic acid, Dermal papilla cells, Anagen, PI3K/Akt, β-Catenin


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