title: Antrodia cinnamomea Inhibits Migration in Human Hepatocellular Carcinoma Cells: The Role of ERp57 and PGK-1.
abstract: Evidences suggest that ERp57 and PGK-1 signaling lead to cancer cell proliferation and migration. We hypothesized that ERp57 and PGK-1 down-regulation may inactivate matrix metalloproteinase (MMP)-2, -9 expressions and inhibit hepatocellular carcinoma (HCC) migration. Antrodia cinnamomea is widely prescribed as an adjuvant to treat HCC in Taiwan. We aimed to investigate if ethanol extract of fruiting bodies of Antrodia cinnamomea (EEAC) and its active ingredients (i.e., zhankuic acid A, cordycepin, and adenosine) can modulate HCC cancer cells migration through ERp57 and PGK-1 and other molecular pathways such as PI3K/Akt and MAPK. ERp57 and PGK-1 siRNA were transfected into HCC to determine effects on MMP-2/-9 expressions and cell migration. We then examined the inhibitory effects of EEAC and its active ingredients on HCC migration and its related mechanisms including ERp57, PGK-1, PI3K/Akt, and MAPK signaling pathways. Down-regulation of ERp57 and PGK-1 by siRNA decreased MMP-2, -9 expressions and Transwell cell migration in HCC. Nontoxic EEAC markedly inhibited migration of HCC, and significantly inhibited activities and protein expressions of MMP-2 and -9, while the expression of the endogenous inhibitors (TIMP-1 and TIMP-2) of these proteins increased. Nontoxic EEAC and its active ingredients decreased ERp57, GLUD-1, GST-pi, and PGK-1 protein expressions. Finally, nontoxic EEAC inhibited the phosphorylated FAK, PI3K/Akt, and MAPK signaling. Our findings first indicate that EEAC and its ingredients effectively suppress HCC migration. Additionally, the molecular mechanisms appear to be mediated, in part, through the down-regulation of ERp57, PGK-1, MAPK, and PI3K/Akt.
authors.affiliation: * School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: * School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Fon-Chang
authors.initials: FC
authors.lastname: Liu
authors.affiliation: † Department of Pharmacy, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.affiliation: * School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Ming-Jyh
authors.initials: MJ
authors.lastname: Sheu
mesh_terms: D055491:Antrodia / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000502:physiology*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D019704:Protein Disulfide-Isomerases / Q000502:physiology*
chemical_list: D010936:Plant Extracts; C577282:PGK1 protein, human; D010735:Phosphoglycerate Kinase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human
keywords: Antrodia cinnamomea; ERp57; Hepatocellular Carcinoma; Migration; PGK-1