Suppression of hypoxia inducible factor-1α (HIF-1α) by YC-1 is dependent on murine double minute 2 (Mdm2)

Inhibition of HIF-1 alpha activity provides an important strategy for the treatment of cancer. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1benzyl 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-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. (c) 2006 Elsevier Inc. All rights reserved.