Small molecules destabilize cIAP1 by activating auto-ubiquitylation.
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 ubiquitin-ligase activity could be a novel strategy to develop small molecules for therapeutic purposes.
Sekine
Keiko
K
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
Takubo
Kohei
K
Kikuchi
Ryo
R
Nishimoto
Michie
M
Kitagawa
Masayuki
M
Abe
Fuminori
F
Nishikawa
Kiyohiro
K
Tsuruo
Takashi
T
Naito
Mikihiko
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*
C529046:(-)-N-((2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl)-L-leucine methyl ester; D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D007930:Leucine