title: Induction of N-myc in neuroblastoma by autocrine IGF-II depends on farnesylated Ras. Application of farnesyltransferase inhibitors.
abstract: Genetic aberrations are the primary events leading to carcinogenesis in various tissues and are characteristic for certain tumor types. Amplification of N-myc and deletion of 1p significantly correlate with poor prognosis of neuroblastoma patients. Very little informations is available on the regulation of N-myc expression by external factors. Insulin-like growth factor-II (IGF-II) has been identified as an autocrine growth factor in neuroblastoma. Four neuroblastoma cell lines were examined for their expression of IGF-II and IGF-receptor. Stimulation of neuroblastoma cells with IGF-II leads to an increased activity of the MAP-kinase Erk1, an induction of N-myc expression and an enhanced proliferation rate. In order to disrupt the signal transduction of the IGF-receptor, we inactivated the Ras-proteins in neuroblastoma cells by inhibition of the farnesyl-protein transferase by FTI-277. This inactivation prevented activation of MAP-kinase Erk1 and induction of N-myc expression by IGF-II. Inactivation of Ras by farnesyltransferase inhibitors might become a promising new approach in future treatments of neuroblastoma tumors.
authors.affiliation: Oncological Laboratory, Department of Pediatric Surgery, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany.
authors.forename: Josefa
authors.initials: J
authors.lastname: Wittrock
authors.forename: Paul
authors.initials: P
authors.lastname: Schweizer
authors.forename: Rainer
authors.initials: R
authors.lastname: Girgert
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D016259:Genes, myc / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017451:Receptors, Somatomedin / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; C096856:FTI 277; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins; D007335:Insulin-Like Growth Factor II; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins