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

Barkan, Batya; Kloog, Yoel; Ehrlich, Marcelo

doi:10.1158/1535-7163.mct-10-1087

Cited by 9 publications

(9 citation statements)

References 43 publications

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“…As shown, the SMAD1/5/8 phosphorylation decreased in ST88NRasKD compared with ST88NonKD, and the siBMP2 can further decrease the SMAD1/5/8 phosphorylation in the ST88NRasKD cell line, which showed the dominant role of BMP2 signaling to control SMAD1/5/8 phosphorylation. Our data are consistent with a recent report indicating that suppression of RAS activity by salirasib, a S-trans, trans-farnesylthiosalicylic acid (FTS), inhibited the expression of Bmp4, and thereafter perturbed BMP4-related SMAD signaling in MPNST cell lines (34). However, we did not find decreased Bmp4 expression after inhibition of NRas by siRNA in our array data.…”

Section: Bmp2 Regulation Of Smad1/5/8 Activity Is Independent Of Nrassupporting

confidence: 93%

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Sun

Haddad

Kraniak

et al. 2013

Molecular Cancer Research

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Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal-regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery. Mol Cancer Res; 11(6); 616-27. Ó2013 AACR.

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Section: Bmp2 Regulation Of Smad1/5/8 Activity Is Independent Of Nrassupporting

confidence: 93%

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Sun

Haddad

Kraniak

et al. 2013

Molecular Cancer Research

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“…It has been reported that farnesyl thiosalicylic acid (FTS), a farnesyl-derived drug [42], could inhibit tumour growth by dislodging oncogenic Ras proteins from cell membranes by competitively binding to the Gal-1 farnesyl-binding site [18,43,44]. However, detailed structural information of the molecular basis for the acting mechanism in tumour growth inhibitory role of FTS is not well understood.…”

Section: Reduced K28t Hgal-1 Has No Farnesyl Binding Abilitymentioning

confidence: 99%

Redox state influence on human galectin-1 function

Scott

Pritchard

et al. 2015

Biochimie

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“…7). Because LIMK1/2 regulation by NF1 is Ras-independent [2, 11, 17, 18], and because we observed a synergistic inhibition of NF1-deficient cell proliferation and stress-fiber formation by combined treatment with T56-LIMKi and the Ras inhibitor FTS (Fig. 5), we propose this combination as a novel approach of potential value for NF1 therapy.…”

Section: Discussionmentioning

confidence: 96%

“…The GRD domain also inhibits a Rho-dependent pathway which activates LIMK2[2, 18]. The pre-GRD domain inhibits the Ras-independent Rac1-activation pathway, which regulates LIMK1[11].…”

Section: Introductionmentioning

confidence: 99%

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Computer-Based Identification of a Novel LIMK1/2 Inhibitor that Synergizes with Salirasib to Destabilize the Actin Cytoskeleton

et al. 2012

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Neurofibromin regulates cell motility via three distinct GTPase pathways acting through two different domains, the Ras GTPase-activating protein-related domain (GRD) and the pre-GRD domain. First, the GRD domain inhibits Ras-dependent changes in cell motility through the mitogen activated protein cascade. Second, it also regulates Rho-dependent (Ras-independent) changes by activating LIM kinase 2 (LIMK2), an enzyme that phosphorylates and inactivates cofilin (an actin-depolymerizing factor). Third, the pre-GRD domain acts through the Rac1 GTPase, that activate the P21 activated kinase 1 (PAK1)-LIMK1-cofilin pathway. We employed molecular modeling to identify a novel inhibitor of LIMK1/2. The active sites of an ephrin-A receptor (EphA3) and LIMK2 showed marked similarity (60%). On testing a known inhibitor of EphA3, we found that it fits to the LIMK1/2-ATP binding site and to the latter's substrate-binding pockets. We identified a similar compound, T56-LIMKi, and found that it inhibits LIMK1/2 kinase activities. It blocked the phosphorylation of cofilin which led to actin severance and inhibition of tumor cell migration, tumor cell growth, and anchorage-independent colony formation in soft agar. Because modulation of LIMK by neurofibromin is not affected by the Ras inhibitor Salirasib, we examined the combined effect of Salirasib and T56-LIMKi each of which can affect cell motility by a distinct pathway. We found that their combined action on cell proliferation and stress-fiber formation in neurofibromin-deficient cells was synergistic. We suggest that this drug combination may be developed for treatment of neurofibromatosis and cancer.

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

Cited by 9 publications

References 43 publications

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Redox state influence on human galectin-1 function

Computer-Based Identification of a Novel LIMK1/2 Inhibitor that Synergizes with Salirasib to Destabilize the Actin Cytoskeleton

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