Small molecules destabilize cIAP1 by activating auto-ubiquitylation
Small molecules destabilize cIAP1 by activating auto-ubiquitylation
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DOI：
10.1074/jbc.m709525200
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发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Naito, Mikihiko
中科院分区：
文献类型：
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作者：
Sekine, Keiko;Takubo, Kohei;Naito, Mikihiko
据报道，在某些癌症中，如肝细胞癌、食管鳞状细胞癌、宫颈癌和肺癌，抗凋亡蛋白 cIAP1 因基因扩增而过度表达，从而对化疗和放疗产生耐药性。在这里，我们报告cIAP1被一类小分子（(-)-N-[(2S,3R)-3-氨基-2-羟基-4-苯基-丁酰基]-L-亮氨酸甲酯（ME-BS））选择性下调，导致癌细胞对细胞凋亡敏感。 ME-BS 直接与 cIAP1 的 BIR3 结构域相互作用，促进依赖于其 RING 结构域的自动泛素化，并促进 cIAP1 的蛋白酶体降解。其他 IAP（例如 XIAP 和 cIAP2）不受 ME-BS 的影响。这些结果表明小分子靶向破坏 cIAP1 的稳定性是治疗表达 cIAP1 的癌症的一种新方法，cIAP1 会干扰治疗。操纵内在泛素连接酶活性可能是开发用于治疗目的的小分子的新策略。
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.