Abstract
During the progression of prostate cancer, the epithelial adhesion molecule E-cadherin is cleaved from the cell surface by ADAM15 proteolytic processing, generating an extracellular 80kDa fragment referred to as soluble E-cadherin (sE-cad). Contrary to observations in cancer, the generation of sE-cad appears to correlate with ADAM10 activity in benign prostatic epithelium. The ADAM10-specific inhibitor INCB8765 and the ADAM10 prodomain inhibit the generation of sE-cad, as well as downstream signaling and cell proliferation. Addition of EGF or amphiregulin (AREG) to these untransformed cell lines increases the amount of sE-cad shed into the conditioned media, as well as sE-cad bound to EGFR. EGF-associated shedding appears to be mediated by ADAM10 as shRNA knockdown of ADAM10 results in reduced shedding of sE-cad. To examine the physiologic role of sE-cad on benign prostatic epithelium, we treated BPH-1 and large T immortalized prostate epithelial cells (PrEC) with an sE-cad chimera comprised of the human Fc domain of IgG(1), fused to the extracellular domains of E-cadherin (Fc-Ecad). The treatment of untransformed prostate epithelial cells with Fc-Ecad resulted in phosphorylation of EGFR and downstream signaling through ERK and increased cell proliferation. Pre-treating BPH-1 and PrEC cells with cetuximab, a therapeutic monoclonal antibody against EGFR, decreased the ability of Fc-Ecad to induce EGFR phosphorylation, downstream signaling, and proliferation. These data suggest that ADAM10-generated sE-cad may have a role in EGFR signaling independent of traditional EGFR ligands.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ADAM Proteins / antagonists & inhibitors
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM10 Protein
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Amphiregulin
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Humanized
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Cadherins / biosynthesis*
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Cadherins / metabolism
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Cell Line
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Cell Proliferation / drug effects
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Cetuximab
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EGF Family of Proteins
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Enzyme Inhibitors / pharmacology
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Epidermal Growth Factor / pharmacology*
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Gene Expression
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Glycoproteins / pharmacology
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Humans
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Immunoglobulin G / genetics
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Immunoglobulin G / pharmacology
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Intercellular Signaling Peptides and Proteins / pharmacology
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Male
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Phosphorylation / drug effects
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Prostate / cytology
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Prostate / drug effects
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Prostate / metabolism*
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Protein Binding
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction* / drug effects
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Solubility
Substances
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AREG protein, human
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Amphiregulin
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Cadherins
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EGF Family of Proteins
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Enzyme Inhibitors
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Glycoproteins
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Immunoglobulin G
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Epidermal Growth Factor
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ErbB Receptors
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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ADAM10 protein, human
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Cetuximab