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

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (178 K)Download as PowerPoint slideHighlights► 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