ABSTRACT
The natural product englerin A (EA) binds to and activates protein kinase C-θ (PKCθ). EA-dependent activation of PKCθ induces an insulin-resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCθ-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors.
Subject(s)
DNA-Binding Proteins/metabolism , Glucose/metabolism , Insulin Resistance , Insulin/metabolism , Isoenzymes/metabolism , Kidney Neoplasms/drug therapy , Protein Kinase C/metabolism , Sesquiterpenes, Guaiane/pharmacology , Signal Transduction/drug effects , Transcription Factors/metabolism , Animals , Apoptosis , Blotting, Western , Cell Proliferation , Heat Shock Transcription Factors , Humans , Immunoprecipitation , Insulin/chemistry , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Mice , Phosphorylation/drug effects , Protein Kinase C-theta , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: The expression of vascular endothelial growth factor (VEGF), a key regulator of angiogenesis, is controlled by the oxygen supply. Previous observations suggested that nicotinic amidoxime derivatives (i.e. BGP-15) might interfere with the induction of hypoxia-sensitive genes. Hence, the effect of BGP-15 on angiogenesis was studied in Hepa 1c1c7 tumor xenografts. MATERIALS AND METHODS: Hepa 1c1c7 hepatoma cells were implanted under the dorsal skin of female CD-1-nu/nu immunodeficient mice. One group of animals was given 100 mg/kg body weight/day BGP-15 intraperitoneally during tumor development. Vascularization, apoptotic and mitotic indices were determined by the histological and immunohistochemical analysis of the tumors. VEGF and GLUT-1 expressions were measured by Northern blot. RESULTS: The in vivo administration of BGP-15 resulted in a decrease in tumor weight and mitotic index, while it did not affect the apoptotic rate in the xenograft. Furthermore, BGP-15 treatment depressed microvascular density and the level of VEGF mRNA by 50%, and similarly decreased GLUT-1 mRNA levels. CONCLUSION: These findings suggest that BGP-15 suppresses hepatoma development by affecting angiogenesis.
