TY  - JOUR
AU  - Phillips, Emma
AU  - Lang, Verena
AU  - Bohlen, Jonathan
AU  - Bethke, Frederic
AU  - Puccio, Laura
AU  - Tichy, Diana
AU  - Herold-Mende, Christel
AU  - Hielscher, Thomas
AU  - Lichter, Peter
AU  - Goidts, Violaine
TI  - Targeting atypical protein kinase C iota reduces viability in glioblastoma stem-like cells via a notch signaling mechanism.
JO  - International journal of cancer
VL  - 139
IS  - 8
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2017-05408
SP  - 1776 - 1787
PY  - 2016
AB  - 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.
KW  - Isoenzymes (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
KW  - Receptors, Notch (NLM Chemicals)
KW  - Protein Kinase C (NLM Chemicals)
KW  - protein kinase C lambda (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27299852
DO  - DOI:10.1002/ijc.30234
UR  - https://inrepo02.dkfz.de/record/130329
ER  -