Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: A mechanism of tumor growth inhibition
Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: A mechanism of tumor growth inhibition
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DOI：
10.1124/mol.106.025817
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发表时间：
2006-11-01
影响因子：
3.6
通讯作者：
Park, Jong-Wan
中科院分区：
文献类型：
--
作者：
Choi, Hyunsung;Chun, Yang-Sook;Park, Jong-Wan
低氧诱导因子-1(HIF-1)是由低氧诱导因子-1α(HIF-1α)和芳烃受体核转运体(ARNT)组成的转录因子，在低氧肿瘤的细胞存活和血管生成中起关键作用，针对HIF-1α的抗癌药物已被大量研究。然而，尽管ARNT也是HIF-1活性所必需的，但ARNT一直被认为是治疗的靶点。姜黄素是一种常用的香料和着色剂，具有多种有益的生物学效应，包括抑制肿瘤。在本研究中，我们测试了姜黄素通过靶向HIF-1抑制肿瘤生长的可能性。研究姜黄素对癌细胞株和移植瘤中HIF-1活性和表达的影响。我们发现姜黄素抑制HIF-1的活性，进而下调HIF-1靶向的基因。此外，在HIF-1的两个亚基中，只有Arnt在几种类型的癌细胞中被姜黄素破坏了稳定性，而且Arnt的表达挽救了姜黄素对HIF-1的抑制。我们还发现，姜黄素通过氧化和泛素化过程刺激Arnt的蛋白酶体降解。在荷有Hep3B肝癌的小鼠中，姜黄素抑制肿瘤生长，并抑制肿瘤中的ARNT、促红细胞生成素和血管内皮生长因子。这些结果表明，姜黄素的抗癌活性可归因于Arnt降解使HIF-1失活。
Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1 alpha and aryl hydrocarbon receptor nuclear translocator (ARNT), plays a key role in cell survival and angiogenesis in hypoxic tumors, and many efforts have been made to develop anticancer agents that target HIF-1 alpha. However, although ARNT is also required for HIF-1 activity, ARNT has been disregarded as a therapeutic target. Curcumin is a commonly used spice and coloring agent with a variety of beneficial biological effects, which include tumor inhibition. In the present study, we tested the possibility that curcumin inhibits tumor growth by targeting HIF-1. The effects of curcumin on HIF-1 activity and expression were examined in cancer cell lines and in xenografted tumors. We found that curcumin inhibits HIF-1 activity and that this in turn down-regulates genes targeted by HIF-1. Moreover, of the two HIF-1 subunits, only ARNT was found to be destabilized by curcumin in several cancer cell types, and furthermore, ARNT expression rescued HIF-1 repression by curcumin. We also found that curcumin stimulated the proteasomal degradation of ARNT via oxidation and ubiquitination processes. In mice bearing Hep3B hepatoma, curcumin retarded tumor growth and suppressed ARNT, erythropoietin, and vascular endothelial growth factor in tumors. These results suggest that the anticancer activity of curcumin is attributable to HIF-1 inactivation by ARNT degradation.