Abstract
Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a very poor prognosis and largely resistant to chemotherapy. MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1. In view of this, MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen-activated protein kinase pathway by the B-Raf inhibitor sorafenib. MPNST (MPNST and ST8814) and dedifferentiated liposarcoma (LS141 and DDLS) human tumor cell lines were characterized for Ras activation and B-Raf expression. Tumor cells were treated with sorafenib and examined for growth inhibition, inhibition of phospho-MEK, phospho-ERK, cell cycle arrest, and changes in cyclin D1 and pRb expression. MPNSTs were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G(1) cell cycle arrest. These effects were not seen in the liposarcoma cells, which either did not express B-Raf or showed decreased Ras activation. Small interfering RNA-mediated depletion of B-Raf in MPNSTs also induced a G(1) cell cycle arrest in these cells, with a marked inhibition of cyclin D1 expression and Rb phosphorylation, whereas depletion of C-Raf did not affect either. With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Benzenesulfonates / pharmacology*
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Blotting, Western
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects*
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase 4 / metabolism
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Flow Cytometry
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G1 Phase / drug effects*
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Gene Silencing
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Humans
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Liposarcoma / drug therapy
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Liposarcoma / enzymology
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Liposarcoma / pathology
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / metabolism
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Nerve Sheath Neoplasms / drug therapy*
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Nerve Sheath Neoplasms / enzymology
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Nerve Sheath Neoplasms / pathology
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Niacinamide / analogs & derivatives
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Phenylurea Compounds
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Phosphorylation
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Proto-Oncogene Proteins B-raf / metabolism
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Proto-Oncogene Proteins c-raf / antagonists & inhibitors
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism
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Pyridines / pharmacology*
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Retinoblastoma Protein / metabolism
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Signal Transduction / drug effects*
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Sorafenib
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ras Proteins / metabolism
Substances
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Antineoplastic Agents
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Benzenesulfonates
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Phenylurea Compounds
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Pyridines
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Retinoblastoma Protein
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Cyclin D1
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Niacinamide
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Sorafenib
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-raf
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CDK4 protein, human
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Cyclin-Dependent Kinase 4
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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ras Proteins