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Gambogic acid covalently interacts with IKK‐2 to inhibit the NF‐kB signaling pathway
Author(s) -
Gandhi Ujjawal H,
Kalantari Parisa,
Palempalli Uma D,
Vunta Hema,
Arner Ryan J,
Prabhu K. Sandeep
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.711.3
Subject(s) - gambogic acid , chemistry , iκb kinase , nf κb , covalent bond , kinase , signal transduction , rna interference , microbiology and biotechnology , gene knockdown , biochemistry , in vitro , rna , gene , biology , organic chemistry
Gambogic acid (GA) is a polyprenylated xanthone abundant in the resin of Garcinia morella and G. hanburyi with a long history of use as a complementary and alternative medicine. The anti‐tumor activity of GA has been well demonstrated and is thought to arise partly due to the anti‐inflammatory activity associated with GA. Here we demonstrate that GA inhibits the LPS‐dependent expression of nuclear factor‐kB (NF‐kB) target pro‐inflammatory genes in murine macrophages. Western immunoblot, NF‐kB luciferase reporter, and gel shift analyses revealed that GA strongly blocked the activation of NF‐kB induced by LPS; while 9,10‐dihydroGA that lacks the reactive alpha,beta‐unsaturated carbonyl group was ineffective. Moreover, GA was able to decrease nuclear p65 levels in RAW264.7 macrophages, where the expression of TfR1 was down‐regulated by RNA interference. In‐vitro kinase assays coupled with interaction studies using biotinylated GA as well as proteomic analysis demonstrated that IKK2, a key kinase of the NF‐ ?ÛB signaling axis, was covalently modified by GA at Cys179 causing significant inhibition of its kinase activity. Taken together, these data demonstrate that covalent modification of IKK2 as an underlying mechanism of the potent anti‐inflammatory activity of GA. NIH AT004350 (KSP)