Activation of the nucleotide oligomerization domain signaling pathway by the non-bacterially derived xanthone drug 5'6-dimethylxanthenone-4-acetic acid (Vadimezan).
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.
Cheng
Guanjun
G
Thoracic Oncology Research Laboratory, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318, USA. guanjun@mail.med.upenn.edu
Sun
Jing
J
Fridlender
Zvi G
ZG
Wang
Liang-Chuan S
LC
Ching
Lai-Ming
LM
Albelda
Steven M
SM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D044004:Xanthones / Q000494:pharmacology*
D000970:Antineoplastic Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D009711:Nucleotides; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044004:Xanthones; C066668:vadimezan; D008156:Luciferases; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; C093642:SB 203580