title: 5'-Nitro-indirubinoxime inhibits epidermal growth factor- and phorbol ester-induced AP-1 activity and cell transformation through inhibition of phosphorylation of Pin1.
abstract: 5'-Nitro-indirubinoxime (5'-NIO), a derivative of indirubin, exhibits anti-cancer activity in a variety of human cancer cells. However, the underlying molecular mechanisms and molecular target(s) of the chemopreventive activities of 5'-NIO remain unknown. Here, we report that 5'-NIO inhibited the epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation of JB6 Cl41 mouse skin epidermal cells without any cytotoxic effects. Western blot analysis revealed that 5'-NIO inhibited activities of Raf-1 (S338), MEK1/2, ERK1/2, JNK, and c-Jun induced by EGF or TPA, respectively, whereas it did not affect autophosphorylation of epidermal growth factor receptor (EGFR) induced by EGF or TPA. In addition, 5'-NIO exerted strong inhibitory effects on the EGF- or TPA-induced c-fos or c-jun transcriptional activity, and thereby inhibited the associated activator protein-1 (AP-1) transactivation activity induced by EGF or TPA. Importantly, 5'-NIO inhibited Pin1 phosphorylation at serine 16 induced by EGF or TPA, respectively, resulted in the inhibition of interaction between Pin1 and Raf-1. Immunoprecipitation/immunoblot analysis revealed that 5'-NIO bound with Pin1. Together, these findings suggest that 5'-NIO might act as an anticarcinogene in EGF- or TPA-induced carcinogenesis through the inhibition of interaction between Pin1 and Raf-1. © 2011 Wiley Periodicals, Inc.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors.forename: Prem
authors.initials: P
authors.lastname: Khanal
authors.forename: Hoo-Kyun
authors.initials: HK
authors.lastname: Choi
authors.forename: Gwang Mo
authors.initials: GM
authors.lastname: Namgoong
authors.forename: Sang-Gun
authors.initials: SG
authors.lastname: Ahn
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Honglae
authors.initials: H
authors.lastname: Sohn
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010091:Oximes / Q000494:pharmacology*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C534713:5'-nitroindirubinoxime; D016588:Anticarcinogenic Agents; D007211:Indoles; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010091:Oximes; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D013755:Tetradecanoylphorbol Acetate