Auranofin, a gold(I)-containing antirheumatic compound, activates Keap1/Nrf2 signaling via Rac1/iNOS signal and mitogen-activated protein kinase activation.
Auranofin (2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-[triethylphosphine] gold) is a gold(I)-containing antirheumatic drug that possesses anti-inflammatory properties. The pharmacological activity of this drug is associated with its ability to induce heme oxygenase-1 (HO-1). However, the mechanism underlying auranofin-mediated HO-1 induction remains unclear. We investigated the action of auranofin on activation of nuclear factor erythroid 2-related factor 2 (Nrf2), an activator of HO-1. Auranofin elevated cellular levels of Nrf2 by increasing protein stability but not transcriptional activation. Coimmunoprecipitation and Western blot analysis indicated that auranofin inhibited Nrf2 degradation by inducing the dissociation of the Nrf2 / Kelch-like ECH-associated protein 1 (Keap1) complex, which resulted in nuclear accumulation of Nrf2. In addition, auranofin treatment activated cellular Rac1 and induced inducible nitric oxide synthase (iNOS) expression. An inhibitor of Rac1 (NSC23766) blocked the iNOS induction as well as Nrf2 activation and HO-1 expression. N(G)-nitro-L-arginine methyl ester and aminoguanidine, inhibitors of iNOS, diminished the auranofin-induced Nrf2 activation and HO-1 expression. Phosphorylation of mitogen-activated protein kinases (MAPKs) was increased by auranofin treatment, and inhibitors of MAPKs partially diminished the Nrf2 activation. A chromatin immunoprecipitation assay showed that the Nrf2 activated by auranofin was involved in transactivation of the HO-1 gene. These findings indicate that auranofin leads to HO-1 upregulation by activating Keap1/Nrf2 signaling via Rac1/iNOS induction and MAPK activation.
Kim
Nam-Hoon
NH
Department of Natural Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Oh
Mi-Kyung
MK
Park
Hyo Jung
HJ
Kim
In-Sook
IS
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C107953:RAC1 protein, human; D012333:RNA, Messenger; D001310:Auranofin; D052247:Nitric Oxide Synthase Type II; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D020830:rac1 GTP-Binding Protein