title: Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway.
abstract: Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK) 1/2 significantly decreased ABG-001-induced neurite outgrowth. Western blot analysis revealed that ABG-001 significantly induced phosphorylation of IGF-1 receptor, protein kinase B (Akt), ERK, and cAMP responsive element-binding protein (CREB). These effects were markedly reduced by addition of the corresponding inhibitors. We also found that ABG-001-induced neurite outgrowth was reduced by protein kinase C inhibitor as well as small-interfering RNA against the IGF-1 receptor. Furthermore, like ABG-001, IGF-1 also induced neurite outgrowth of PC12 cells, and low-dose nerve growth factor augmented the observed effects of ABG-001 on neurite outgrowth. These results suggest that ABG-001 targets the IGF-1 receptor and activates PI3K, mitogen-activated protein kinase, and their downstream signaling cascades to induce neurite outgrowth.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.).
authors.forename: Ruiqi
authors.initials: R
authors.lastname: Tang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.).
authors.forename: Lijuan
authors.initials: L
authors.lastname: Gao
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.).
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.).
authors.forename: Xueli
authors.initials: X
authors.lastname: Cao
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.).
authors.forename: Lan
authors.initials: L
authors.lastname: Xiang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China (R.T., L.G., J.C., X.C., L.X., J.Q.); and Chemical Biology Core Facility, RIKEN, Advanced Science Institute, Saitama, Japan (M.K., H.O.) qijianhua@zju.edu.cn.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D062385:Hydroxybenzoates / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
chemical_list: D062385:Hydroxybenzoates; C571109:tetradecyl-2,3-dihydroxybenzoate; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1