title: Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival.
abstract: Merlin is a tumour suppressor involved in the development of a variety of tumours including mesotheliomas. Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, is also caused by loss of merlin. NF2 patients suffer from multiple genetically well-defined tumours, schwannomas are most frequent among those. Using our in vitro model for human schwannoma, we found that schwannoma cells display enhanced proliferation because of the overexpression/activation of platelet-derived growth factor receptor and ErbB2/3, increased cell-matrix adhesion because of the overexpression of integrins, and decreased apoptosis. Mechanisms underlying schwannomas basal proliferation and cell-matrix adhesion are not understood. Here, we investigated insulin-like growth factor-binding protein-1 (IGFBP-1), which is expressed and released from central nervous system tumours and strongly overexpressed in schwannoma at the mRNA level. IGFBP-1 acts via β1-integrin and focal-adhesion-kinase (FAK), which are strongly overexpressed and basally activated in schwannoma. Using short hairpin RNA knockdown, small inhibitors and recombinant IGFBP-1, we demonstrate that schwannoma cells, in contrast to Schwann cells, release IGFBP-1 that activates the Src/FAK pathway, via integrin β1, potentiating schwannoma's proliferation and cell-matrix adhesion. We show that FAK localizes to the nucleus and Src triggers IGFBP-1 production. Further, we observed downregulation of the tumour-suppressor phosphatase and tensin homolog in schwannoma cells leading to increased activity of anti-apoptotic AKT. Thus, IGFBP-1/integrin β1/Src/FAK pathway has a crucial role in merlin-related tumourigenesis and therefore represents an important therapeutic target in the treatment of merlin-deficient tumours.
authors: Clinical Neurobiology, Peninsula College for Medicine and Dentistry, Plymouth, UK.
authors: S
authors: S
authors: Ammoun
authors: M C
authors: MC
authors: Schmid
authors: L
authors: L
authors: Zhou
authors: N
authors: N
authors: Ristic
authors: E
authors: E
authors: Ercolano
authors: D A
authors: DA
authors: Hilton
authors: C M
authors: CM
authors: Perks
authors: C O
authors: CO
authors: Hanemann
mesh_terms: D002448:Cell Adhesion; D049109:Cell Proliferation; D002470:Cell Survival; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D009442:Neurilemmoma / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018970:Insulin-Like Growth Factor Binding Protein 1; D008565:Membrane Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D051058:Oncogene Protein v-akt; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase