Abstract
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.
Highlights
IAPs are a family of antiapoptotic proteins containing one to three baculoviral IAP repeat (BIR)2 domains [1,2,3], some of which are frequently overexpressed in malignant cells
We describe selective down-regulation of cIAP1 by esterified analogs of bestatin represented by bestatin-methyl ester (ME-BS), resulting in a sensitization of cancer cells to apoptosis
IAPs are a family of anti-apoptotic proteins that are frequently overexpressed in cancer cells [1,2,3]
Summary
Reagents and Plasmids—ME-BS and analogs of bestatin were synthesized by Nippon Kayaku Co. The cell lysates were analyzed by Western blot with the indicated antibodies. Because the proteasome degrades poly-ubiquitylated proteins, we examined ubiquitylation of cIAP1 in ME-BS treated cells. S.D. The lower panels show the down-regulation of cIAP1 in HT1080 cells stably expressing FLAG-tagged co-treated with ME-BS and MG132. The cells were treated with 15 M bestatin analogs for 3 h, and the cell lysates were analyzed by Western blot (WB) with the indicated antibodies. The lower panels show the down-regulation of endogenous cIAP1
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