LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line
LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line
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DOI：
10.1016/j.bcp.2010.06.018
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发表时间：
2010-10-01
影响因子：
5.8
通讯作者：
Won, Misun
中科院分区：
文献类型：
--
作者：
Lee, Kyeong;Kang, Jung Eun;Won, Misun
低氧诱导因子HIF-1在肿瘤治疗中起辐射抵抗和不良预后的作用。作为我们药物发现计划的一部分，一种新型的HIF抑制剂LW6被鉴定为一种抑制HIF-1α积累的小化合物。我们发现，LW6降低了HIF-1α蛋白的表达，而不影响HIF-1β的表达。蛋白酶体抑制剂MG132可保护HIF-1α免受LW6诱导的蛋白酶体降解，表明LW6影响HIF-1α蛋白的稳定性。我们发现，LW6促进了野生型HIF-1α的降解，但不能通过P402A和P564A的修饰促进DM-HIF-1α的降解。LW6不影响Prolyl羟基酶(PHD)的活性，但诱导von Hippel-Lindau(VHL)的表达，VHL与Prolyl羟化的HIF-1α相互作用，参与蛋白酶体的降解。在LW6存在的情况下，敲除VHL并不能消除HIF-1α的蛋白积聚，表明LW6通过调节VHL的表达来降解HIF-1α。在携带人结肠癌HCT116细胞异种移植瘤的小鼠中，LW6在体内表现出强大的抗肿瘤效果，并导致冰冻组织免疫组化染色中HIF-1α的表达减少。这些数据表明，LW6在开发用于癌症治疗的HIF-1α抑制剂方面可能有价值。(C)2010 Elsevier Inc.保留所有权利。
Hypoxia-inducible factor HIF-1 is responsible for radiation resistance and poor prognosis in cancer therapy. As part of our drug discovery program, a novel HIF inhibitor, LW6, was identified as a small compound that inhibits the accumulation of HIF-1 alpha. We found that LW6 decreased HIF-1 alpha protein expression without affecting HIF-1 beta expression. MG132, a proteasome inhibitor, protected HIF-1 alpha from LW6-induced proteasomal degradation, indicating that LW6 affects the stability of the HIF-1 alpha protein. We found that LW6 promoted the degradation of wild type HIF-1 alpha, but not of a DM-HIF-1 alpha with modifications of P402A and P564A, at hydroxylation sites in the oxygen-dependent degradation domain (ODDD). LW6 did not affect the activity of prolyl hydroxylase (PHD), but induced the expression of von Hippel-Lindau (VHL), which interacts with prolyl-hydroxylated HIF-1 alpha for proteasomal degradation. In the presence of LW6, knockdown of VHL did not abolish HIF-1 alpha protein accumulation, indicating that LW6 degraded HIF-1 alpha via regulation of VHL expression. In mice carrying xenografts of human colon cancer HCT116 cells, LW6 demonstrated strong anti-tumor efficacy in vivo and caused a decrease in HIF-1 alpha expression in frozen-tissue immunohistochemical staining. These data suggest that LW6 may be valuable in the development of a HIF-1 alpha inhibitor for cancer treatment. (C) 2010 Elsevier Inc. All rights reserved.