Jesterone dimer, a synthetic derivative of the fungal metabolite jesterone, blocks activation of transcription factor nuclear factor kappaB by inhibiting the inhibitor of kappaB kinase.
Rel/nuclear factor-kappaB (NF-kappaB) transcription factors control a variety of cellular processes, such as cell growth and apoptosis, and are continually activated in many human diseases, including chronic inflammatory diseases and cancer. Jesterone dimer (JD) is a synthetic derivative of the natural fungal metabolite jesterone, and JD has previously been shown to be cytotoxic in select tumor cell lines. In this report, we demonstrate that JD is a potent inhibitor of the activation of transcription factor NF-kappaB. Namely, JD inhibits tumor necrosis factor-alpha-induced activation of NF-kappaB in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-kappaB pathway by inhibiting the inhibitor of kappaB kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IkappaBalpha, inhibits the activity of a constitutively active form of the IKKbetacatalytic subunit, and converts IKKbetato stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-kappaB at 20 microM, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-kappaB at this concentration. Finally, JD inhibits both proliferation and DNA binding by REL-containing complexes in the human lymphoma SUDHL-4 cell line, and JD activates caspase-3 activity in these cells. In summary, these results suggest that JD induces apoptosis in tumor cells through a mechanism that involves the inhibition of Rel/NF-kappaB activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.
Liang
Mei-Chih
MC
Department of Biology, Boston University, Boston, Massachusetts, USA.
Bardhan
Sujata
S
Li
Chaomin
C
Pace
Emily A
EA
Porco
John A
JA
Gilmore
Thomas D
TD
D016475:3T3 Cells; D000475:Alkenes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D004347:Drug Interactions; D004852:Epoxy Compounds / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000475:Alkenes; D004273:DNA, Neoplasm; D004852:Epoxy Compounds; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; C431025:jesterone; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse