title: Phosphoinositol 3-kinase, a novel target molecule for the inhibitory             effects of juglone on TPA-induced cell transformation.
abstract: Juglone (5-hydroxy-1,4-naphthalenedione) from black walnut trees induces apoptosis and inhibits proliferation of various malignant cells. Here, we investigated whether juglone affects 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation through the phosphoinositol 3-kinase (PI3K) pathway. The results showed that TPA- and endothelial growth factor (EGF)-induced anchorage-independent colony formation were suppressed in a dose-dependent manner by treatment of JB6 CI41 mouse skin epidermal cells with juglone (2.5 and 5 µM). We demonstrated that juglone suppressed PI3K activity via direct binding to PI3K by sepharose 4B pull-down assay and western blot analysis. Juglone significantly suppressed TPA-induced protein kinase B (AKT) and c-Jun phosphorylation and c-fos activation, but not mitogen-activated protein-kinase kinase (MEK), extracellular signaling-regulated kinase (ERK) or 90 kDa ribosomal protein S6 kinase (RSK) phosphorylation. Juglone significantly blocked activator protein-1 (AP-1) and cyclooxygenase-2 (COX-2) activation more than the PI3K inhibitors LY294002 and wortmannin. Overall, these results showed the anticancer efficacy of juglone targeting PI3K to prevent TPA-induced tumorigenesis.
authors.affiliation: Department of Oral Pharmacology, School of Dentistry and Institute                     of Oral Bioscience, BK21 Project, Chonbuk National University, Jeonju,                     Republic of Korea.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Cho
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Kyung-Ae
authors.initials: KA
authors.lastname: Lee
authors.forename: Moon-Kyun
authors.initials: MK
authors.lastname: Cho
authors.forename: Hae-Seon
authors.initials: HS
authors.lastname: Nam
authors.forename: Kee-Min
authors.initials: KM
authors.lastname: Woo
authors.forename: Sang-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016228:Endothelial Growth Factors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009285:Naphthoquinones / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D052246:Cyclooxygenase 2 Inhibitors; D016228:Endothelial Growth Factors; D009025:Morpholines; D009285:Naphthoquinones; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051546:Cyclooxygenase 2; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C005134:juglone; D000077191:Wortmannin