Suppression of hypoxia inducible factor-1{alpha} (HIF-1{alpha}) by YC-1 is dependent on murine double minute 2 (Mdm2)
- Center for the Study of Liver Disease and Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong (China)
Inhibition of HIF-1{alpha} activity provides an important strategy for the treatment of cancer. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) has been identified as an anti-HIF-1{alpha} drug in cancer therapy with unclear molecular mechanism. In the present study, we aimed to investigate the effect and mechanism of YC-1 on HIF-1{alpha} in a hepatocellular carcinoma cell line under hypoxic condition, which was generated by incubating cells with 0.1% O{sub 2}. The phenotypic and molecular changes of cells were determined by cell proliferation assay, apoptosis assay, luciferase promoter assay, and Western blot analysis. YC-1 arrested tumor cell growth in a dose-dependent manner, whereas it did not induce cell apoptosis. Hypoxia-induced upregulation of HIF-1{alpha} was suppressed by YC-1 administration. YC-1 inhibited HIF-1{alpha} protein synthesis under normoxia and affected protein stability under hypoxia. YC-1 suppressed the expression of total and phosphorylated forms of murine double minute 2 (Mdm2), whereas this inhibitory effect was blocked by overexpression of Mdm2. In conclusion, YC-1 suppressed both protein synthesis and stability of HIF-1{alpha} in HCC cells, and its inhibitory effects on HIF-1{alpha} were dependent on Mdm2.
- OSTI ID:
- 20854508
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 348, Issue 4; Other Information: DOI: 10.1016/j.bbrc.2006.08.015; PII: S0006-291X(06)01805-5; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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