RT Journal Article
SR Electronic
T1 Jesterone Dimer, a Synthetic Derivative of the Fungal Metabolite Jesterone, Blocks Activation of Transcription Factor Nuclear Factor κB by Inhibiting the Inhibitor of κB Kinase
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 123
OP 131
DO 10.1124/mol.64.1.123
VO 64
IS 1
A1 Mei-Chih Liang
A1 Sujata Bardhan
A1 Chaomin Li
A1 Emily A. Pace
A1 John A. Porco, Jr
A1 Thomas D. Gilmore
YR 2003
UL http://molpharm.aspetjournals.org/content/64/1/123.abstract
AB Rel/nuclear factor-κB (NF-κB) 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-κB. Namely, JD inhibits tumor necrosis factor-α–induced activation of NF-κB in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-κB pathway by inhibiting the inhibitor of κB kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IκBα, inhibits the activity of a constitutively active form of the IKKβcatalytic subunit, and converts IKKβto stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-κB at 20 μM, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-κB 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-κB activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.