Englerin A stimulates PKCθ to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality

  • Cancer Cell. 2013 Feb 11;23(2):228-37. doi: 10.1016/j.ccr.2012.12.007.
Carole Sourbier  1 ,  Bradley T Scroggins ,  Ranjala Ratnayake ,  Thomas L Prince ,  Sunmin Lee ,  Min-Jung Lee ,  Peter Literati Nagy ,  Young H Lee ,  Jane B Trepel ,  John A Beutler ,  W Marston Linehan ,  Len Neckers
Affiliations
  • 1. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
PMID: 23352416 DOI: 10.1016/j.ccr.2012.12.007
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.

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