title: Suppression of AMF/PGI-mediated tumorigenic activities by ursolic acid in cultured hepatoma cells and in a mouse model.
abstract: Our previous studies demonstrated that autocrine motility factor/phosphoglucose isomerase (AMF/PGI) possesses tumorigenic activities through the modulation of intracellular signaling. We then investigated the effects of ursolic acid (UA), oleanolic acid (OA), tangeretin, and nobiletin against AMF/PGI-mediated oncogenesis in cultured stable Huh7 and Hep3B cells expressing wild-type or mutated AMF/PGI and in a mouse model in this study. The working concentrations of the tested compounds were lower than their IC10 , which was determined by Brdu incorporation and colony formation assay. Only UA efficiently suppressed the AMF/PGI-induced Huh7 cell migration and MMP-3 secretion. Additionally, UA inhibited the AMF/PGI-mediated protection against TGF-β-induced apoptosis in Hep3B cells, whereas OA, tangeretin, and nobiletin had no effect. In Huh7 cells and tumor tissues, UA disrupted the Src/RhoA/PI 3-kinase signaling and complex formation induced by AMF/PGI. In the Hep3B system, UA dramatically suppressed AMF/PGI-induced anti-apoptotic signaling transmission, including Akt, p85, Bad, and Stat3 phosphorylation. AMF/PGI enhances tumor growth, angiogenesis, and pulmonary metastasis in mice, which is correlated with its enzymatic activity, and critically, UA intraperitoneal injection reduces the tumorigenesis in vivo, enhances apoptosis in tumor tissues and also prolongs mouse survival. Combination of sub-optimal dose of UA and cisplatin, a synergistic tumor cell-killing effects was found. Thus, UA modulates intracellular signaling and might serve as a functional natural compound for preventing or alleviating hepatocellular carcinoma.
authors.affiliation: Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan.
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Shih
authors.forename: Feng-Ling
authors.initials: FL
authors.lastname: Yu
authors.forename: Ching-Dong
authors.initials: CD
authors.lastname: Chang
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Liao
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Wu
authors.forename: Ping-Yuan
authors.initials: PY
authors.lastname: Lin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004195:Disease Models, Animal; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D047309:Flavones / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009828:Oleanolic Acid / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000097245:Ursolic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D002945:Cisplatin; D047309:Flavones; D005956:Glucose-6-Phosphate Isomerase; D008156:Luciferases; D019278:Matrix Metalloproteinase 3; D009828:Oleanolic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016212:Transforming Growth Factor beta; D014315:Triterpenes; D020742:rhoA GTP-Binding Protein; D000097245:Ursolic Acid; C008661:nobiletin; C059006:tangeretin