Englerin A Stimulates PKCθ to Inhibit Insulin Signaling and to Simultaneously Activate HSF1: Pharmacologically Induced Synthetic Lethality

• Published in: Cancer cell 2013-02, Vol.23 (2), p.228-237
• Main Authors: Sourbier, Carole, Scroggins, Bradley T., Ratnayake, Ranjala, Prince, Thomas L., Lee, Sunmin, Lee, Min-Jung, Nagy, Peter Literati, Lee, Young H., Trepel, Jane B., Beutler, John A., Linehan, W. Marston, Neckers, Len
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blotting, Western; Cell Proliferation; DNA-Binding Proteins - metabolism; Glucose - metabolism; Heat Shock Transcription Factors; Humans; Immunoprecipitation; Insulin - chemistry; Insulin - metabolism; Insulin Resistance; Isoenzymes - metabolism; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Mice; Phosphorylation - drug effects; Protein Kinase C - metabolism; Protein Kinase C-theta; Sesquiterpenes, Guaiane - pharmacology; Signal Transduction - drug effects; Transcription Factors - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2012.12.007

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. [Display omitted] ► EA activates PKCθ ► PKCθ inhibits the insulin pathway and glucose uptake in tumor cells ► PKCθ activates HSF1 to enhance the glucose dependence of tumor cells ► EA is synthetically lethal for glycolytic tumor cells expressing PKCθ and HSF1