Cycloprodigiosin hydrocloride suppresses tumor necrosis factor (TNF) alpha-induced transcriptional activation by NF-kappaB.
Cycloprodigiosin hydrochloride (cPrG.HCl) obtained from a marine bacterium Pseudoalteromonas denitrificans induces apoptotic cell death in various cancerous cell lines. cPrG.HCl alone caused a little cytotoxicity in HeLa cells, but it enhanced the apoptotic process progressively when co-administered with tumor necrosis factor (TNF)alpha. Here we studied the effect of cPrG.HCl on TNFalpha-induced activation of the transcription factor nuclear factor kappaB (NF-kappaB). Luciferase gene reporter assays revealed that cPrG.HCl potently suppressed the TNFalpha- and the phorbol myristate acetate-induced activation of NF-kappaB. The suppression occurred in the presence of imidazole, indicating that it was not related to the intracellular acidification resulting from the intrinsic H(+)/Cl(-) symporter activity of cPrG.HCl. cPrG.HCl inhibited neither the TNFalpha-induced phosphorylation and degradation of inhibitor of nuclear factor-kappaB, nor the subsequent nuclear translocation and DNA binding of NF-kappaB. cPrG.HCl also suppressed NF-kappaB-enhanced gene expression induced by Rac1, Cdc42, MEKK1, inhibitor of nuclear factor-kappaalpha (IKKalpha), IKKbeta, and a subunit of NF-kappaB, p65. These results indicate that cPrG.HCl suppresses NF-kappaB-dependent gene expression through the inhibition of transcriptional activation.
Kamata
K
K
Department of Life Science, Faculty of Science, Himeji Institute of Technology, kamigori-chou, Akoh-gun, 678-1297, Hyogo, Japan.
Okamoto
S
S
Oka
S
S
Kamata
H
H
Yagisawa
H
H
Hirata
H
H
D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D048728:MAP Kinase Kinase Kinase 1; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics
D007211:Indoles; D016328:NF-kappa B; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; C108328:cycloprodigiosin; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D013755:Tetradecanoylphorbol Acetate