nsc-134754 and Breast-Neoplasms

nsc-134754 has been researched along with Breast-Neoplasms* in 1 studies

Other Studies

1 other study(ies) available for nsc-134754 and Breast-Neoplasms

ArticleYear
Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway.
    Cancer research, 2006, Jun-15, Volume: 66, Issue:12

    Overexpression of hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1alpha versus HIF-2alpha to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1alpha and/or HIF-2alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1alpha and/or HIF-2alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1alpha and HIF-2alpha expression in hypoxia in these cells: HIF-2alpha siRNA enhanced HIF-1alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1alpha and HIF-2alpha due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2alpha protein expression and HIF-2alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically.

    Topics: Basic Helix-Loop-Helix Transcription Factors; Breast Neoplasms; Carcinoma, Renal Cell; Cell Hypoxia; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Targeting; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin-Like Growth Factor I; Isoquinolines; Kidney Neoplasms; RNA, Small Interfering; Transcription Factors; Transcriptional Activation; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

2006