Abstract
The semaphorin guidance molecules and their receptors, the plexins, are often inappropriately expressed in cancers. However, the signaling processes mediated by plexins in tumor cells are still poorly understood. Here, we demonstrate that the Semaphorin 3E (Sema3E) regulates tumor cell survival by suppressing an apoptotic pathway triggered by the Plexin D1 dependence receptor. In mouse models of breast cancer, a ligand trap that sequesters Sema3E inhibited tumor growth and reduced metastasis through a selective tumor cytocidal effect. We further showed that Plexin D1 triggers apoptosis via interaction with the orphan nuclear receptor NR4A1. These results define a critical role of Sema3E/Plexin D1 interaction in tumor resistance to apoptosis and suggest a therapeutic approach based on activation of a dependence receptor pathway.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Apoptosis*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Caspase 3 / metabolism
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Cell Adhesion Molecules, Neuronal / physiology*
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Cell Line, Tumor
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Female
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary*
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Membrane Glycoproteins
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
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Peptide Fragments / chemistry
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Peptide Fragments / pharmacology
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Peptide Fragments / physiology
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Protein Interaction Domains and Motifs
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Semaphorins / chemistry
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Semaphorins / pharmacology
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Semaphorins / physiology*
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Signal Transduction
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Cell Adhesion Molecules, Neuronal
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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NR4A1 protein, human
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Nuclear Receptor Subfamily 4, Group A, Member 1
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PLXND1 protein, human
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Peptide Fragments
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SEMA3E protein, human
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Semaphorins
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CASP3 protein, human
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Caspase 3