Phenotypic Reversion of Invasive Neurofibromin-Deficient Schwannoma by FTS: Ras Inhibition Reduces BMP4/Erk/Smad Signaling

作者：Barkan Batya; Kloog Yoel^*; Ehrlich Marcelo

来源：Molecular Cancer Therapeutics, 2011, 10(8): 1317-1326.

DOI：10.1158/1535-7163.MCT-10-1087

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-beta. 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-beta and BMP signaling. FTS perturbed signaling of BMP4 and TGF-beta 1 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-defficient cells by FTS. Inhibition of BMP4 and TGF-beta 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-beta 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-beta pathway inhibitors, toward the inhibition of mitogenic and morphogenic signaling pathways and the alleviation of NF1 symptoms. Mol Cancer Ther; 10(8); 1317-26.

• 出版日期2011-8