Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis.
Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.
Shishodia
Shishir
S
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Aggarwal
Bharat B
BB
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins; D008956:Models, Chemical; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011282:Pregnenediones / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013696:Temperature; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011282:Pregnenediones; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; C023617:pregna-4,17-diene-3,16-dione; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011065:Poly(ADP-ribose) Polymerases; D013755:Tetradecanoylphorbol Acetate