Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1). We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1-GRD) suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Curcumin / pharmacology*
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Nerve Sheath Neoplasms / complications
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Nerve Sheath Neoplasms / drug therapy
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Nerve Sheath Neoplasms / genetics*
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Nerve Sheath Neoplasms / metabolism
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Neurofibromatosis 1 / complications
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Neurofibromatosis 1 / drug therapy
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Neurofibromatosis 1 / genetics*
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Neurofibromatosis 1 / metabolism
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Neurofibromin 1 / antagonists & inhibitors
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Neurofibromin 1 / deficiency
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Neurofibromin 1 / genetics*
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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Schwann Cells / drug effects
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Schwann Cells / metabolism
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Schwann Cells / pathology
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Signal Transduction / drug effects
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Substances
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Antineoplastic Agents, Phytogenic
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Cell Cycle Proteins
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MAD1L1 protein, human
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MYC protein, human
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Neurofibromin 1
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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Reactive Oxygen Species
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Curcumin
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Acetylcysteine
Grants and funding
This work was supported by the Bundesministerium für Bildung und Forschung (BMBF) program rare diseases (grant 01GM0841). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.