Englerin A stimulates PKCθ to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality.
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.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Carole
C
Sourbier
Bradley T
BT
Scroggins
Ranjala
R
Ratnayake
Thomas L
TL
Prince
Sunmin
S
Lee
Min-Jung
MJ
Lee
Peter Literati
PL
Nagy
Young H
YH
Lee
Jane B
JB
Trepel
John A
JA
Beutler
W Marston
WM
Linehan
Len
L
Neckers
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D045789:Sesquiterpenes, Guaiane / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D007328:Insulin; D007527:Isoenzymes; D045789:Sesquiterpenes, Guaiane; D014157:Transcription Factors; C534971:englerin A; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D005947:Glucose