title: Madecassoside suppresses proliferation and invasiveness of HGF-induced human hepatocellular carcinoma cells via PKC-cMET-ERK1/2-COX-2-PGE2 pathway.
abstract: Recent studies showed that Madecassoside (MAD), a pentacyclic triterpene isolated from Centella asitica (L.), was used as a therapeutic agent in wound healing and also as an anti-inflammatory, anti-oxidative activities and anti-aging agent. However, its role in cancer has not been elucidated. In our present study, hepatocyte growth factor (HGF) induced the phosphorylation of its corresponding receptor cMET, increased expression of cyclo-oxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in human hepatocellular carcinoma (HCC) cells lines (HepG2 and SMMC-77), and this effect was inhibited by MAD in a dose-dependent manner. In addition, MAD exhibited significant anti-proliferative and anti-invasive effect in HGF-induced HepG2 and SMMC-77 cells. Moreover, MAD inhibited the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the protein kinase C (PKC) activity in HGF-induced HepG2 and SMMC-77 cells. This conclusion was consistent with the effect of selective COX-2 inhibitor (NS-398) and knockdown of COX-2 by siRNA on attenuating the proliferation and invasiveness potential, and over-expression of COX-2 on abolishing the effects of MAD on proliferation and invasiveness potential, and was also in parallel with the effect of PKC inhibitor (Bisindolylmaleimide) on inhibiting PKC activity, MEK/ERK1/2 inhibitor (PD98059) inhibited MEK/ERK1/2 pathways in HGF-induced HepG2 and SMMC-77 cells. Collectively, MAD could inhibit the HGF-activated proliferation and invasiveness of HCC cells via regulating the activation of cMET-PKC-ERK1/2-COX-2-PGE2 cascade, which indicated that MAD might help control HGF-linked HCC.
authors: Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100 Weihui, Henan, China.
authors: Zexin
authors: Z
authors: Li
authors: Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100 Weihui, Henan, China.
authors: Kun
authors: K
authors: You
authors: Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100 Weihui, Henan, China.
authors: Jian
authors: J
authors: Li
authors: Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100 Weihui, Henan, China.
authors: Ying
authors: Y
authors: Wang
authors: Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100 Weihui, Henan, China.
authors: Hongwei
authors: H
authors: Xu
authors: Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100 Weihui, Henan, China.
authors: Baoqin
authors: B
authors: Gao
authors: Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100 Weihui, Henan, China. Electronic address: wangjianguohn@163.com.
authors: Jianguo
authors: J
authors: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D028041:Centella / Q000276:immunology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D009361:Neoplasm Invasiveness; D009578:Nitrobenzenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009578:Nitrobenzenes; D034741:RNA, Small Interfering; D013449:Sulfonamides; D014315:Triterpenes; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D017228:Hepatocyte Growth Factor; C093443:madecassoside; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone
keywords: Hepatocellular carcinoma; Hepatocyte growth factor; Invasiveness; Madecassoside; Proliferation; Protein kinase C