Targeting atypical protein kinase C iota reduces viability in glioblastoma stem-like cells via a notch signaling mechanism.
In a previous study, Protein Kinase C iota (PRKCI) emerged as an important candidate gene for glioblastoma (GBM) stem-like cell (GSC) survival. Here, we show that PKCι is overexpressed and activated in patient derived GSCs compared with normal neural stem cells and normal brain lysate, and that silencing of PRKCI in GSCs causes apoptosis, along with loss of clonogenicity and reduced proliferation. Notably, PRKCI silencing reduces tumor growth in vivo in a xenograft mouse model. PKCι has been intensively studied as a therapeutic target in non-small cell lung cancer, resulting in the identification of an inhibitor, aurothiomalate (ATM), which disrupts the PKCι/ERK signaling axis. However, we show that, although sensitive to pharmacological inhibition via a pseudosubstrate peptide inhibitor, GSCs are much less sensitive to ATM, suggesting that PKCι acts along a different signaling axis in GSCs. Gene expression profiling of PRKCI-silenced GSCs revealed a novel role of the Notch signaling pathway in PKCι mediated GSC survival. A proximity ligation assay showed that Notch1 and PKCι are in close proximity in GSCs. Targeting PKCι in the context of Notch signaling could be an effective way of attacking the GSC population in GBM.
DKFZ Junior Group Brain Tumor Translational Targets, German Cancer Research Center, Heidelberg, Germany.
Emma
E
Phillips
Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
Verena
V
Lang
Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
Jonathan
J
Bohlen
DKFZ Junior Group Brain Tumor Translational Targets, German Cancer Research Center, Heidelberg, Germany.
Frederic
F
Bethke
DKFZ Junior Group Brain Tumor Translational Targets, German Cancer Research Center, Heidelberg, Germany.
Laura
L
Puccio
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
Diana
D
Tichy
Division of Experimental Neurosurgery, University of Heidelberg, Germany.|Department of Neurosurgery, University of Heidelberg, Germany.
Christel
C
Herold-Mende
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
Thomas
T
Hielscher
DKFZ Junior Group Brain Tumor Translational Targets, German Cancer Research Center, Heidelberg, Germany.
Peter
P
Lichter
DKFZ Junior Group Brain Tumor Translational Targets, German Cancer Research Center, Heidelberg, Germany.
Violaine
V
Goidts
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051880:Receptors, Notch / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
D007527:Isoenzymes; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D051880:Receptors, Notch; D000099293:Protein Kinase C-lambda
atypical protein kinase C iota; glioblastoma; glioblastoma stem-like cells; notch signaling