20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginsenoside Rb1, enhances the production of hyaluronic acid through the activation of ERK and Akt mediated by Src tyrosin kinase in human keratinocytes

Lim,Tae-Gyu; Jeon,Ae  Ji; Yoon,Ji Hye; Song,Dasom; Kim,Jong-Eun; Kwon,Jung Yeon; Kim,Jong Rhan; Kang,Nam  Joo; Park,Jun-Seong; Yeom,Myeong Hun; Oh,Deok-Kun; Lim,Yoongho; Lee,Charles   C.; Lee,Chang  Yong; Lee,Ki  Won

doi:10.3892/ijmm.2015.2121

20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginsenoside Rb1, enhances the production of hyaluronic acid through the activation of ERK and Akt mediated by Src tyrosin kinase in human keratinocytes

Authors:
- Tae-Gyu Lim
- Ae Ji Jeon
- Ji Hye Yoon
- Dasom Song
- Jong-Eun Kim
- Jung Yeon Kwon
- Jong Rhan Kim
- Nam Joo Kang
- Jun-Seong Park
- Myeong Hun Yeom
- Deok-Kun Oh
- Yoongho Lim
- Charles C. Lee
- Chang Yong Lee
- Ki Won Lee
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Affiliations: Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270, Republic of Korea, Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea, WCU Biomodulation Major, Department of Agricultural Biotechnology and Institute on Aging, Seoul National University, Seoul 151-921, Republic of Korea, School of Food Science and Biotechnology, Kyungpook National University, Daegu 702-701, Republic of Korea, Skin Research Institute, Amorepacific Corporation R&D Center, Yongin 341-1, Republic of Korea, Department of Food Science, Cornell University, Ithaca, NY 14850, USA
Published online on: March 2, 2015 https://doi.org/10.3892/ijmm.2015.2121
Pages: 1388-1394

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Abstract

The aim of the present study was to determine the mechanisms through which 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol (20GPPD) promotes the production of hyaluronic acid (HA) in human keratinocytes. 20GPPD is the primary bioactive metabolite of Rb1, a major ginsenoside found in ginseng (Panax ginseng). We sought to elucidate the underlying mechanisms behind the 20GPPD-induced production of HA. We found that 20GPPD induced an increase in HA production by elevating hyaluronan synthase 2 (HAS2) expression in human keratinocytes. The phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was also enhanced by 20GPPD in a dose-dependent manner. The pharmacological inhibition of ERK (using U0126) or Akt (using LY294002) suppressed the 20GPPD-induced expression of HAS2, whereas treatment with an epidermal growth factor receptor (EGFR) inhibitor (AG1478) or an intracellular Ca2+ chelator (BAPTA/AM) did not exert any observable effects. The increased Src phosphorylation was also confirmed following treatment with 20GPPD in the human keratinocytes. Following pre-treatment with the Src inhibitor, PP2, both HA production and HAS2 expression were attenuated. Furthermore, the 20GPPD-enhanced ERK and Akt signaling decreased following treatment with PP2. Taken together, our results suggest that Src kinase plays a critical role in the 20GPPD-induced production of HA by acting as an upstream modulator of ERK and Akt activity in human keratinocytes.

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1	Christensen LP: Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res. 55:1–99. 2009. View Article : Google Scholar
2	Kim WK, Song SY, Oh WK, et al: Wound-healing effect of ginsenoside Rd from leaves of Panax ginseng via cyclic AMP-dependent protein kinase pathway. Eur J Pharmacol. 702:285–293. 2013. View Article : Google Scholar : PubMed/NCBI
3	Kimura Y, Sumiyoshi M, Kawahira K and Sakanaka M: Effects of ginseng saponins isolated from Red Ginseng roots on burn wound healing in mice. Br J Pharmacol. 148:860–870. 2006. View Article : Google Scholar : PubMed/NCBI
4	Lee HS, Kim MR, Park Y, et al: Fermenting red ginseng enhances its safety and efficacy as a novel skin care anti-aging ingredient: in vitro and animal study. J Med Food. 15:1015–1023. 2012. View Article : Google Scholar : PubMed/NCBI
5	He D, Sun J, Zhu X, Nian S and Liu J: Compound K increases type I procollagen level and decreases matrix metalloproteinase-1 activity and level in ultraviolet-A-irradiated fibroblasts. J Formos Med Assoc. 110:153–160. 2011. View Article : Google Scholar : PubMed/NCBI
6	Lou JS, Chen XE, Zhang Y, et al: Photoprotective and immunoregulatory capacity of ginsenoside Rg1 in chronic ultraviolet B-irradiated BALB/c mouse skin. Exp Ther Med. 6:1022–1028. 2013.PubMed/NCBI
7	Cai BX, Jin SL, Luo D, Lin XF and Gao J: Ginsenoside Rb1 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. Biol Pharm Bull. 32:837–841. 2009. View Article : Google Scholar : PubMed/NCBI
8	Cai BX, Luo D, Lin XF and Gao J: Compound K suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair in human keratinocytes. Arch Pharm Res. 31:1483–1488. 2008. View Article : Google Scholar : PubMed/NCBI
9	Cuong TT, Yang CS, Yuk JM, et al: Glucocorticoid receptor agonist compound K regulates Dectin-1-dependent inflammatory signaling through inhibition of reactive oxygen species. Life Sci. 85:625–633. 2009. View Article : Google Scholar : PubMed/NCBI
10	Kim S, Kang BY, Cho SY, et al: Compound K induces expression of hyaluronan synthase 2 gene in transformed human keratinocytes and increases hyaluronan in hairless mouse skin. Biochem Biophys Res Commun. 316:348–355. 2004. View Article : Google Scholar : PubMed/NCBI
11	Hwang JA, Hwang MK, Jang Y, et al: 20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginseng, inhibits colon cancer growth by targeting TRPC channel-mediated calcium influx. J Nutr Biochem. 24:1096–1104. 2013. View Article : Google Scholar : PubMed/NCBI
12	Laurent TC and Fraser JR: Hyaluronan. FASEB J. 6:2397–2404. 1992.PubMed/NCBI
13	Oe M, Mitsugi K, Odanaka W, et al: Dietary hyaluronic acid migrates into the skin of rats. Scientific World Journal. 2014:3780242014. View Article : Google Scholar : PubMed/NCBI
14	Toole BP: Hyaluronan in morphogenesis. J Intern Med. 242:35–40. 1997. View Article : Google Scholar : PubMed/NCBI
15	Pasonen-Seppänen SM, Maytin EV, Törrönen KJ, et al: All-trans retinoic acid-induced hyaluronan production and hyperplasia are partly mediated by EGFR signaling in epidermal keratinocytes. J Invest Dermatol. 128:797–807. 2008. View Article : Google Scholar
16	Stern R and Maibach HI: Hyaluronan in skin: aspects of aging and its pharmacologic modulation. Clin Dermatol. 26:106–122. 2008. View Article : Google Scholar : PubMed/NCBI
17	Tammi RH and Tammi MI: Hyaluronan accumulation in wounded epidermis: a mediator of keratinocyte activation. J Invest Dermatol. 129:1858–1860. 2009. View Article : Google Scholar : PubMed/NCBI
18	Weigel PH, Hascall VC and Tammi M: Hyaluronan synthases. J Biol Chem. 272:13997–14000. 1997. View Article : Google Scholar : PubMed/NCBI
19	Spicer AP and McDonald JA: Characterization and molecular evolution of a vertebrate hyaluronan synthase gene family. J Biol Chem. 273:1923–1932. 1998. View Article : Google Scholar : PubMed/NCBI
20	Camenisch TD, Spicer AP, Brehm-Gibson T, et al: Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest. 106:349–360. 2000. View Article : Google Scholar : PubMed/NCBI
21	Tammi RH, Passi AG, Rilla K, et al: Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J. 278:1419–1428. 2011. View Article : Google Scholar : PubMed/NCBI
22	Pasonen-Seppänen S, Karvinen S, Törrönen K, et al: EGF upregulates, whereas TGF-beta downregulates, the hyaluronan synthases Has2 and Has3 in organotypic keratinocyte cultures: correlations with epidermal proliferation and differentiation. J Invest Dermatol. 120:1038–1044. 2003. View Article : Google Scholar : PubMed/NCBI
23	Li L, Asteriou T, Bernert B, Heldin CH and Heldin P: Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB. Biochem J. 404:327–336. 2007. View Article : Google Scholar : PubMed/NCBI
24	Thomas SM and Brugge JS: Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 13:513–609. 1997. View Article : Google Scholar : PubMed/NCBI
25	Bourguignon LY, Zhu H, Shao L and Chen YW: CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J Biol Chem. 276:7327–7336. 2001. View Article : Google Scholar
26	Schlessinger J: New roles for Src kinases in control of cell survival and angiogenesis. Cell. 100:293–296. 2000. View Article : Google Scholar : PubMed/NCBI
27	Stuhlmeier KM and Pollaschek C: Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. J Biol Chem. 279:8753–8760. 2004. View Article : Google Scholar
28	Monslow J, Sato N, Mack JA and Maytin EV: Wounding-induced synthesis of hyaluronic acid in organotypic epidermal cultures requires the release of heparin-binding egf and activation of the EGFR. J Invest Dermatol. 129:2046–2058. 2009. View Article : Google Scholar : PubMed/NCBI
29	Oh JH, Kim YK, Jung JY, Shin JE and Chung JH: Changes in glycosaminoglycans and related proteoglycans in intrinsically aged human skin in vivo. Exp Dermatol. 20:454–456. 2011. View Article : Google Scholar : PubMed/NCBI
30	Zhang L, Teng Y, Zhang Y, et al: C-Src-mediated RANKL-induced breast cancer cell migration by activation of the ERK and Akt pathway. Oncol Lett. 3:395–400. 2012.PubMed/NCBI
31	Liu G, Hitomi H, Hosomi N, et al: Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway. J Hypertens. 29:696–705. 2011. View Article : Google Scholar : PubMed/NCBI
32	Paek IB, Moon Y, Kim J, et al: Pharmacokinetics of a ginseng saponin metabolite compound K in rats. Biopharm Drug Dispos. 27:39–45. 2006. View Article : Google Scholar
33	Karvinen S, Pasonen-Seppänen S, Hyttinen JM, et al: Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3. J Biol Chem. 278:49495–49504. 2003. View Article : Google Scholar : PubMed/NCBI
34	Kim do Y, Park MW, Yuan HD, Lee HJ, Kim SH and Chung SH: Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells. J Agric Food Chem. 57:10573–10578. 2009. View Article : Google Scholar : PubMed/NCBI
35	Lee JH, Jeong SM, Kim JH, et al: Effects of ginsenosides and their metabolites on voltage-dependent Ca(2+) channel subtypes. Mol Cells. 21:52–62. 2006.PubMed/NCBI
36	Saavalainen K, Pasonen-Seppänen S, Dunlop TW, Tammi R, Tammi MI and Carlberg C: The human hyaluronan synthase 2 gene is a primary retinoic acid and epidermal growth factor responding gene. J Biol Chem. 280:14636–14644. 2005. View Article : Google Scholar : PubMed/NCBI
37	Tang ZN, Zhang F, Tang P, Qi XW and Jiang J: RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation. Oncol Rep. 26:1243–1250. 2011.PubMed/NCBI
38	Zhuang S, Duan M and Yan Y: Src family kinases regulate renal epithelial dedifferentiation through activation of EGFR/PI3K signaling. J Cell Physiol. 227:2138–2144. 2012. View Article : Google Scholar
39	Yang CX, Liu YW, He YQ and Gao F: Src kinase-MAPK signal pathway plays a role in proliferation of endothelial cells induced by o-HA. Fen Zi Xi Bao Sheng Wu Xue Bao. 39:495–501. 2006.In Chinese.
40	Vigetti D, Deleonibus S, Moretto P, et al: Role of UDP-N-acetylglucosamine (GlcNAc) and O-GlcNAcylation of hyaluronan synthase 2 in the control of chondroitin sulfate and hyaluronan synthesis. J Biol Chem. 287:35544–35555. 2012. View Article : Google Scholar : PubMed/NCBI