title: A steric blocker of translation elongation inhibits IGF-1R expression and cell transformation.
abstract: The insulin-like growth factor 1 receptor (IGF-1R) is involved in transformation, survival, mitogenesis and differentiation. It is overexpressed in many tumors and a validated target for anticancer therapy. In cell-free systems, polypyrimidic peptide nucleic acids (PNAs) can form triplex-like structures with messenger RNAs and halt the ribosomal machinery during the translation elongation. A 17-mer PNA that formed a PNA(2):mRNA complex with a purine-rich sequence located in the coding region of IGF-1R mRNA induced the synthesis of a truncated IGF-1R in vitro. This PNA down-regulated expression of the receptor by 70-80% in prostate cancer cells without affecting insulin receptor expression that exhibits high homology with IGF-1R. Inhibition occurs at the translational level, since the IGF-1R mRNA level measured by quantitative RT-PCR was not affected by PNA treatment. In addition, IGF-1R knockdown by PNA led to an attenuation of phosphorylation of downstream signaling pathways, PI3K/AKT and MAPK, involved in survival and mitogenesis and also to a decrease in cell transformation. Of the steric blockers tested, which included phosphorodiamidate morpholino oligomers and locked nucleic acids, PNA was unique in its ability to form triplex structures with mRNA and to arrest translation elongation.
authors.affiliation: Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Unité Mixte de Recherche 7196, Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Lecosnier
authors.forename: Céline
authors.initials: C
authors.lastname: Cordier
authors.forename: Philippe
authors.initials: P
authors.lastname: Simon
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: François
authors.forename: Tula E
authors.initials: TE
authors.lastname: Saison-Behmoaras
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002474:Cell-Free System; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020135:Peptide Nucleic Acids / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014410:Tumor Stem Cell Assay
chemical_list: D020135:Peptide Nucleic Acids; D011687:Purines; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3