title: Phenotypic reversion of invasive neurofibromin-deficient schwannoma by FTS: Ras inhibition reduces BMP4/Erk/Smad signaling.
abstract: Neurofibromin-deficient (Nf1(-/-)) malignant peripheral nerve sheath tumors (MPNST) are highly invasive, refractory to chemotherapy, and characterized by overactivated Ras. Ras activates mitogenic pathways and regulates morphogenic programs--such as those induced by bone morphogenetic proteins (BMP) and TGF-β. The role of such a cross-talk in determining the phenotype and transformation potential of MPNSTs is unknown. Here, we used MPNST cell lines and selective Ras inhibition with S-trans,trans-farnesylthiosalicylic-acid (FTS; salirasib) in conjunction with specific inhibitors of TGF-β and BMP signaling. FTS perturbed signaling of BMP4 and TGF-β1 to Smad-dependent and Erk-dependent pathways. Furthermore, FTS inhibited motility and spreading, reduced the gelatinase secretion, eliminated the expression and activation of regulators of cell-matrix interaction, and altered gene expression. These phenomena are indicative of a phenotypic reversion of NF1-deficient cells by FTS. Inhibition of BMP4 and TGF-β by noggin and SB-431542, respectively, mimicked the FTS-mediated effects on adhesion, spreading, and cell morphology. This strongly suggests that a cross-talk among TGF-β superfamily ligands and Ras plays a significant role in the transformation of NF1(-/-) MPNSTs. Our results support the therapeutic potential of FTS, in conjuncture with BMP and TGF-β pathway inhibitors, toward the inhibition of mitogenic and morphogenic signaling pathways and the alleviation of NF1 symptoms.
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Batya
authors.initials: B
authors.lastname: Barkan
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009442:Neurilemmoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics*; D010641:Phenotype; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D055415:Bone Morphogenetic Protein 4; D025542:Neurofibromin 1; D012459:Salicylates; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins