Abstract
A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / metabolism
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B-Cell CLL-Lymphoma 10 Protein
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism
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Caspase Inhibitors
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Caspases / genetics
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Caspases / metabolism*
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Cell Line, Tumor
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Cell Proliferation
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Guanylate Cyclase / genetics
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Guanylate Cyclase / metabolism
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Humans
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Lung Neoplasms / enzymology*
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Lymphoma, Large B-Cell, Diffuse / enzymology*
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Mice
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis
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Proto-Oncogene Mas
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Signal Transduction / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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B-Cell CLL-Lymphoma 10 Protein
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BCL10 protein, human
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CARD Signaling Adaptor Proteins
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Caspase Inhibitors
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MAS1 protein, human
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NF-kappa B
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Neoplasm Proteins
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Proto-Oncogene Mas
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Caspases
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MALT1 protein, human
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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CARD11 protein, human
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Guanylate Cyclase