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.
Highlights
Phenotypic alterations and dedifferentiation of cancer cells are critical in malignancy and increase the invasive/ metastatic attributes of tumors [1]
TGF-b1 protein was reduced to approximately 60% of that in control cells (P < 0.01, n 1⁄4 4). These results suggest the Ras-mediated regulation of TGF-b and BMP4 signaling in NF1-deficient cells
To determine whether BMP4 and/or TGF-b1 activate Ras signaling cascades, we examined the activation of Erk1/2, an established node of cross-talk among these pathways [37] and a regulator of cell spreading and motility [38]
Summary
Phenotypic alterations and dedifferentiation of cancer cells are critical in malignancy and increase the invasive/ metastatic attributes of tumors [1]. Active Ras drives tumor progression through deregulation of proliferation and phenotypic transformation [2]. Altered phenotypic regulation of cancers cells, such as the epithelial-to-mesenchymal transition (EMT) of epithelial tumors, results from the integration of developmental or morphogenic signaling pathways with those induced by deregulated Ras [3]. Authors' Affiliations: Departments of 1Neurobiology and 2Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Y. Kloog is the incumbent of the Jack H.
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