Abstract
The cytosolic nucleotide-binding oligomerization domain 1 (NOD1)/CARD4 and NOD2/CARD15 proteins are members of NOD-like receptors recognizing specific motifs within peptidoglycans of both Gram-negative and Gram-positive bacteria. NOD1 and NOD2 signal via the downstream adaptor serine/threonine kinase RIP2/CARDIAK/RICK to initiate NF-kappaB activation and the release of inflammatory cytokines/chemokines. In this report, we show that 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a cell-permeable, small molecule that has anti-tumor activity, can also activate NOD1 and NOD2. This was demonstrated: 1) by using human embryonic kidney epithelial (HEK) 293 cells transfected with a NF-kappaB reporter plasmid in combination with NOD1 or NOD2 expression plasmids; 2) by inhibiting DMXAA-induced chemokine (CXCL10) mRNA and protein production in the AB12 mesothelioma cell line using a pharmacological inhibitor of RICK kinase, SB20358; and 3) by using small interfering RNA to knock down NOD2 and lentiviral short hairpin RNA to knock down RICK. These findings expand the potential ligands for the NOD-like receptors, suggesting that other xanthone compounds may act similarly and could be developed as anti-tumor agents. This information also expands our knowledge on the mechanisms of action of the anti-tumor agent DMXAA (currently in clinical trials) and may be important for its biological activity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / pharmacology*
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Cells, Cultured
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Chemokine CXCL10 / genetics
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Chemokine CXCL10 / metabolism
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Enzyme Inhibitors / pharmacology
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Humans
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Imidazoles / pharmacology
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Immunoblotting
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Kidney / cytology
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Kidney / metabolism
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Luciferases / metabolism
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Mesothelioma / genetics
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Mesothelioma / metabolism
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Mesothelioma / pathology
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Nod1 Signaling Adaptor Protein / antagonists & inhibitors
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Nod1 Signaling Adaptor Protein / genetics
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Nod1 Signaling Adaptor Protein / metabolism*
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Nod2 Signaling Adaptor Protein / antagonists & inhibitors
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Nod2 Signaling Adaptor Protein / genetics
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Nod2 Signaling Adaptor Protein / metabolism*
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Nucleotides / metabolism*
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Pyridines / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / antagonists & inhibitors
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects*
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Xanthones / pharmacology*
Substances
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Antineoplastic Agents
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CXCL10 protein, human
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Chemokine CXCL10
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Enzyme Inhibitors
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Imidazoles
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NF-kappa B
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NOD1 protein, human
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NOD2 protein, human
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Nod1 Signaling Adaptor Protein
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Nod2 Signaling Adaptor Protein
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Nucleotides
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Pyridines
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RNA, Messenger
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RNA, Small Interfering
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Xanthones
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vadimezan
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Luciferases
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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SB 203580