Abstract
One of the main functions of A Disintegrin and Metalloproteinase 10 (ADAM10) is to regulate the bioavailability of adhesion molecules and ligands to various cellular-signaling receptors. Constitutive activation of ADAM10 has been implicated in the pathogenesis of several types of solid tumors. In this study, we found that mantle cell lymphoma (MCL) cell lines and all 12 patient samples examined expressed the active/mature form of ADAM10. In contrast, PBMCs from healthy donors (n = 5) were negative. Using immunohistochemistry, ADAM10 was readily detectable in 20 of 23 (87%) MCL tumors, but absent in 5 reactive tonsils. Knockdown of ADAM10 using short interfering RNA (siRNA) in MCL cells significantly induced growth inhibition and cell-cycle arrest, and these changes were correlated with down-regulation of cyclin D1, up-regulation of p21(waf1), and significant reductions in the TNFα production/transcriptional activity of NFκBp65. The addition of recombinant ADAM10 to MCL cells led to the opposite biologic effects. Lastly, down-regulation of ADAM10 using siRNA enhanced the growth-suppressing effects mediated by the proteasome inhibitors MG132 and bortezomib. We conclude that constitutive activation of ADAM10 contributes to the growth of MCL and therefore inhibition of ADAM10 may be a useful strategy to enhance the response of MCL to other therapeutic agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM10 Protein
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Boronic Acids / pharmacology
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Bortezomib
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Cell Line, Tumor
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Female
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Humans
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Leupeptins / pharmacology
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Lymphoma, Mantle-Cell / genetics
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Lymphoma, Mantle-Cell / metabolism*
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Palatine Tonsil / metabolism
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Pyrazines / pharmacology
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Signal Transduction
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Tonsillar Neoplasms / genetics
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Tonsillar Neoplasms / metabolism*
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Boronic Acids
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CCND1 protein, human
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cysteine Proteinase Inhibitors
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Leupeptins
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Membrane Proteins
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Proteasome Inhibitors
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Pyrazines
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RELA protein, human
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Cyclin D1
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Bortezomib
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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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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde