Identification of a Novel Small Molecule HIF-1α Translation Inhibitor

被引:106
作者
Narita, Takuhito
Yin, Shaoman
Gelin, Christine F. [6 ,7 ,8 ]
Moreno, Carlos S. [3 ]
Yepes, Manuel [4 ,5 ]
Nicolaou, K. C. [6 ,7 ,8 ]
Van Meir, Erwin G. [1 ,2 ]
机构
[1] Emory Univ, Sch Med, Winship Canc Inst,Lab Mol Neurooncol, Mol Pathways & Biomarkers Program,Dept Neurosurg, Atlanta, GA 30322 USA
[2] Emory Univ, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA
[3] Emory Univ, Dept Pathol & Lab Med, Winship Canc Inst, Atlanta, GA 30322 USA
[4] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA
[5] Emory Univ, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA
[6] Univ Calif San Diego, Dept Chem, Scripps Res Inst, La Jolla, CA USA
[7] Univ Calif San Diego, Skaggs Inst Chem Biol, Scripps Res Inst, La Jolla, CA USA
[8] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
关键词
HYPOXIA-INDUCIBLE FACTOR; GROWTH-FACTOR EXPRESSION; CELL-CYCLE ARREST; CANCER-CELLS; FACTOR; 1-ALPHA; PSAMMAPLIN-A; FACTOR-I; CARBONIC-ANHYDRASES; HUMAN GLIOMA; PATHWAY;
D O I
10.1158/1078-0432.CCR-08-3180
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Purpose: Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular response to low oxygen, functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is overexpressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1 alpha inhibitor was identified and its molecular mechanism was investigated. Experimental Design: Using a HIF-responsive reporter cell-based assay, a 10,000-member natural product-like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation, and protein degradation processes were analyzed. Results: KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast, and prostate cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as carbonic anhydrase IX, matrix metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into the mechanism of action of KC7F2 showed that it worked through the down-regulation of HIF-1 alpha protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and p70 S6 kinase, key regulators of HIF-1 alpha protein synthesis. Conclusion: These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study. (Clin Cancer Res 2009;15 (19):6128-36)
引用
收藏
页码:6128 / 6136
页数:9
相关论文
共 67 条
[1]
A natural histone deacetylase inhibitor, Psammaplin A, induces cell cycle arrest and apoptosis in human endometrial cancer cells [J].
Ahn, Mee Young ;
Jung, Jee H. ;
Na, Yong Jin ;
Kim, Hyung Sik .
GYNECOLOGIC ONCOLOGY, 2008, 108 (01) :27-33
[2]
Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes [J].
Altenberg, B ;
Greulich, KO .
GENOMICS, 2004, 84 (06) :1014-1020
[3]
CELL INACTIVATION AND CELL-CYCLE INHIBITION AS INDUCED BY EXTREME HYPOXIA - THE POSSIBLE ROLE OF CELL-CYCLE ARREST AS A PROTECTION AGAINST HYPOXIA-INDUCED LETHAL DAMAGE [J].
AMELLEM, O ;
PETTERSEN, EO .
CELL PROLIFERATION, 1991, 24 (02) :127-141
[4]
Hypoxia inducible factor-1: a novel target for cancer therapy [J].
Belozerov, VE ;
Van Meir, EG .
ANTI-CANCER DRUGS, 2005, 16 (09) :901-909
[5]
Belozerov VE, 2006, CURR OPIN INVEST DR, V7, P1067
[6]
Brennan PA, 2000, ANN ROY COLL SURG, V82, P363
[7]
trans-3,4,5′-trihydroxystibene inhibits hypoxia-inducible factor 1α and vascular endothelial growth factor expression in human ovarian cancer cells [J].
Cao, ZX ;
Fang, J ;
Xia, C ;
Shi, XL ;
Jiang, BH .
CLINICAL CANCER RESEARCH, 2004, 10 (15) :5253-5263
[8]
Comerford KM, 2002, CANCER RES, V62, P3387
[9]
EKER P, 1964, RADIAT RES, P165
[10]
Current development of mTOR inhibitors as anticancer agents [J].
Faivre, Sandrine ;
Kroemer, Guido ;
Raymond, Eric .
NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (08) :671-688