title: Suppression of hypoxia inducible factor-1alpha (HIF-1alpha) by YC-1 is dependent on murine double minute 2 (Mdm2).
abstract: Inhibition of HIF-1alpha 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-1alpha 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-1alpha 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-1alpha was suppressed by YC-1 administration. YC-1 inhibited HIF-1alpha 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-1alpha in HCC cells, and its inhibitory effects on HIF-1alpha were dependent on Mdm2.
authors.affiliation: Center for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Chi Keung
authors.initials: CK
authors.lastname: Lau
authors.forename: Zhen Fan
authors.initials: ZF
authors.lastname: Yang
authors.forename: Chi Tat
authors.initials: CT
authors.lastname: Lam
authors.forename: Ka Ho
authors.initials: KH
authors.lastname: Tam
authors.forename: Ronnie Tung Ping
authors.initials: RT
authors.lastname: Poon
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D051736:Proto-Oncogene Proteins c-mdm2