title: In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A.
abstract: One of the two isoforms of the human insulin receptor (isoform A or IR-A) binds IGF-II with high affinity and is predominantly expressed in fetal tissues and malignant cells. We evaluated the biological relevance of IR-A in human myosarcoma cells. Six myosarcoma cell lines were studied. All produced high amounts of IGF-II and five of them predominantly expressed IR-A. SKUT-1 leiomyosarcoma cells, that do not express the IGF-IR, were identified as a suitable model to study the effects of IR-A in the absence of the interference of IGF-IR. In these cells, which express high levels of IR with an IR-A relative abundance of approximately 95%, IGF-II elicits biological effects exclusively via IR-A activation and IGF-I is almost ineffective. Blockade of autocrine IGF-II reduced unstimulated cell viability and migration. Although both insulin and IGF-II activate IR-A, these two ligands showed a different ability to activate different intracellular signaling pathways and to elicit different biological effects. Insulin was more potent than IGF-II in activating the PI3-K/Akt pathway and in protecting cells from apoptosis. In contrast, IGF-II was more potent than insulin in activating the Shc/ERK pathway and in stimulating cell migration. These data indicate that IGF-II sensitive IR-A is the predominant IR isoform in a variety of myosarcoma cells. In SKUT-1 leiomyoma cells this fetal IR isoform may vicariate the IGF-IR for cell response to both insulin and IGF-II. Acting on the same IR-A receptor IGF-II is more potent than insulin in stimulating cancer cell migration.
authors.affiliation: Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, Ospedale Garibaldi, 95123 Catania, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Sciacca
authors.forename: Rossana
authors.initials: R
authors.lastname: Mineo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pandini
authors.forename: Antonella
authors.initials: A
authors.lastname: Murabito
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vigneri
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
mesh_terms: D015703:Antigens, CD; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D007335:Insulin-Like Growth Factor II / Q000502:physiology*; D007890:Leiomyosarcoma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C072216:TRS1 protein, Human herpesvirus 5; D014764:Viral Proteins; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt