Targeting atypical protein kinase C iota reduces viability in glioblastoma stem-like cellsviaa notch signaling mechanism

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Abstract

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.

What's new?

Increased understanding of gene expression patterns in glioblastoma (GBM) has led to the identification of genes involved in survival, among them protein kinase C iota (PRKCI). PRKCI is classified as an oncogene in several human cancer types. In this study, PRKCI was found to be overexpressed in patient-derived GBM stem-like cells (GSCs) and to play a crucial role in GSC survival through Notch signaling. Its silencing slowed tumor growth and prolonged survival in a xenograft GBM mouse model. The findings highlight the therapeutic promise of PKCι and its potential to provide a new avenue for GSC-targeted GBM therapies.

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