Binding of manumycin A inhibits IkappaB kinase beta activity.

Abstract

IkappaB kinase (IKK) catalytic subunits play a key role in cytokinemediated nuclear factor (NF)-kappaB signaling, and a loss of NF-kappaB function appears to inhibit inflammation and oncogenesis. Manumycin A is a potent and selective farnesyltransferase inhibitor with antitumor activity. We found that manumycin A caused a rapid and potent inhibition of IKK activity induced by tumor necrosis factor alpha in a number of cell types. Most unexpectedly, other classes of farnesyltransferase inhibitors had no inhibitory effect. To identify the molecular mechanisms of manumycin A action, cultured human HepG2 hepatoma cells were transiently transfected with various IKKalpha and IKKbeta constructs, and a striking difference in manumycin A sensitivity was observed. Furthermore, cells expressing wild-type IKKbeta and IKKbeta mutated in the activation loop at Cys-179 exhibited covalent homotypic dimerization of IKKbeta in response to manumycin A, whereas substitution of Cys-662 and -716 conferred protection against dimer formation. Direct inhibition of IKK activity and formation of stable IKKbeta dimers were observed in the presence of manumycin A that could be blocked by dithiothreitol. IKK interaction with the adaptor protein IKKgamma/NEMO was disrupted in manumycin A-treated cells. Most importantly, administration of manumycin A to mice xenografted with murine B16F10 tumors caused potent IKK-suppressive effects. Thus, manumycin A with its epoxyquinoid moieties plays an important regulatory function in IKK signaling through pathways distinct from its role as a protein farnesylation inhibitor.

• Authors: Michel Bernier, Yong-Kook Kwon, Sanjay K Pandey, Tie-Nian Zhu, Rui-Jing Zhao, Alexandre Maciuk, Hua-Jun He, Rafael Decabo, Sutapa Kole
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 5 Pg. 2551-61 (Feb 03 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16319058 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Polyenes
• Polyunsaturated Alkamides
• Tumor Necrosis Factor-alpha
• I-kappa B Kinase
• manumycin

Topics

• Amino Acid Substitution
• Animals
• Cell Line, Tumor
• Dimerization
• Humans
• I-kappa B Kinase (antagonists & inhibitors, genetics)
• Mice
• Neoplasms, Experimental (drug therapy)
• Polyenes (pharmacology, therapeutic use)
• Polyunsaturated Alkamides
• Protein Binding
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)