title: Sinulariolide Suppresses Human Hepatocellular Carcinoma Cell Migration and Invasion by Inhibiting Matrix Metalloproteinase-2/-9 through MAPKs and PI3K/Akt Signaling Pathways.
abstract: Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigate the migration and invasion effects of sinulariolide in hepatocellular carcinoma cell HA22T. Sinulariolide inhibited the migration and invasion effects of hepatocellular carcinoma cells in a concentration-dependent manner. The results of zymography assay showed that sinulariolide suppressed the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Moreover, protein levels of MMP-2, MMP-9, and urokinase-type plasminogen activator (uPA) were reduced by sinulariolide in a concentration-dependent manner. Sinulariolide also exerted an inhibitory effect on phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK), phosphatidylinositol 3-kinase (PI3K), Akt, Focal adhesion kinase (FAK), growth factor receptor-bound protein 2 (GRB2). Taken together, these results demonstrated that sinulariolide could inhibit hepatocellular carcinoma cell migration and invasion and alter HA22T cell metastasis by reduction of MMP-2, MMP-9, and uPA expression through the suppression of MAPKs, PI3K/Akt, and the FAK/GRB2 signaling pathway. These findings suggest that sinulariolide merits further evaluation as a chemotherapeutic agent for human hepatocellular carcinoma.
authors.affiliation: Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan. x00002180@meiho.edu.tw.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Department of Research, Pingtung Christian Hospital, Pingtung 90059, Taiwan. neohca@gmail.com.
authors.forename: Choo-Aun
authors.initials: CA
authors.lastname: Neoh
authors.affiliation: Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 94450, Taiwan. tsao-chiayu@umail.hinet.net.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Tsao
authors.affiliation: Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 94450, Taiwan. x2219@nmmba.gov.tw.|Industry Academia Collaboration Center, National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan. x2219@nmmba.gov.tw.
authors.forename: Jui-Hsin
authors.initials: JH
authors.lastname: Su
authors.affiliation: Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 94450, Taiwan. hhli@nmmba.gov.tw.|Industry Academia Collaboration Center, National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan. hhli@nmmba.gov.tw.
authors.forename: Hsing-Hui
authors.initials: HH
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; C050253:sinulariolide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Sinularia flexibilis; hepatocellular carcinoma (HCC); invasion; matrix metalloproteinase-2/-9; migration; sinulariolide