Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation

• Published in: The Journal of biological chemistry Vol. 283; no. 14; pp. 8961 - 8968
• Main Authors: Sekine, Keiko, Takubo, Kohei, Kikuchi, Ryo, Nishimoto, Michie, Kitagawa, Masayuki, Abe, Fuminori, Nishikawa, Kiyohiro, Tsuruo, Takashi, Naito, Mikihiko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.04.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; Humans; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - metabolism; Leucine - analogs & derivatives; Leucine - pharmacology; Neoplasms - drug therapy; Neoplasms - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Structure, Tertiary; Ubiquitin - metabolism; Ubiquitination - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M709525200

Overexpression of an anti-apoptotic protein cIAP1 caused by its genetic amplification was reported in certain cancers, such as hepatocellular carcinoma, esophageal squamous cell carcinoma, cervical cancer, and lung cancer, which confers resistance to chemotherapy and radiotherapy. Here we report cIAP1 to be selectively down-regulated by a class of small molecules ((–)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-l-leucine methyl ester (ME-BS)), resulting in a sensitization of cancer cells to apoptosis. ME-BS directly interacts with the BIR3 domain of cIAP1, promotes auto-ubiquitylation dependent on its RING domain, and facilitates proteasomal degradation of cIAP1. Other IAPs such as XIAP and cIAP2 were not affected by ME-BS. These results suggest targeted destabilization of cIAP1 by small molecules as a novel method to treat cancers expressing cIAP1, which interferes with treatment. Manipulation of the intrinsic ubiquitinligase activity could be a novel strategy to develop small molecules for therapeutic purposes.