Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: abrogation of cyclooxygenase-2 and matrix metalloprotease-9.
Betulinic acid (BA), a pentacyclic triterpene isolated from the bark of the white birch tree, has been reported to be a selective inducer of apoptosis in tumor cells. It also exhibits anti-inflammatory and immunomodulatory properties. How BA mediates these effects is not known. Because of the critical role of the transcription factor NF-kappaB in growth modulatory, inflammatory, and immune responses, we postulated that BA modulates the activity of this factor. In this study we investigated the effect of BA on NF-kappaB and NF-kappaB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. BA suppressed NF-kappaB activation induced by TNF, PMA, cigarette smoke, okadaic acid, IL-1, and H(2)O(2). The suppression of NF-kappaB activation was not cell-type specific. BA suppressed the activation of IkappaBalpha kinase, thus abrogating the phosphorylation and degradation of IkappaBalpha. We found that BA inhibited NF-kappaB activated by TNFR 1, TNFR-associated death domain, TNFR-associated factor 2, NF-kappaB-inducing kinase, and IkappaBalpha kinase. Treatment of cells with this triterpinoid also suppressed NF-kappaB-dependent reporter gene expression and the production of NF-kappaB-regulated gene products such as cyclooxygenase-2 and matrix metaloproteinase-9 induced by inflammatory stimuli. Furthermore, BA enhanced TNF-induced apoptosis. Overall, our results indicated that BA inhibits activation of NF-kappaB and NF-kappaB-regulated gene expression induced by carcinogens and inflammatory stimuli. This may provide a molecular basis for the ability of BA to mediate apoptosis, suppress inflammation, and modulate the immune response.
Takada
Yasunari
Y
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Aggarwal
Bharat B
BB
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002273:Carcinogens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D051546:Cyclooxygenase 2; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014026:Nicotiana / Q000633:toxicity; D051996:Transcription Factor RelA; D014315:Triterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D012906:Smoke; D051996:Transcription Factor RelA; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D019319:Okadaic Acid; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; D000094062:Betulinic Acid