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. Epub 2013 Jan 23.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 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

Substances

  • DNA-Binding Proteins
  • Heat Shock Transcription Factors
  • Hsf1 protein, mouse
  • Insulin
  • Isoenzymes
  • Sesquiterpenes, Guaiane
  • Transcription Factors
  • englerin A
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-theta
  • Glucose