Document Type
Article
Publication Date
11-1-2020
Keywords
JGM, JAXCC
JAX Source
Am J Cancer Res 2020 Nov 1; 10(11):3765-3783
Volume
10
Issue
11
First Page
3765
Last Page
3783
ISSN
2156-6976
PMID
33294266
Abstract
The Cdc2-like kinases (CLKs) regulate RNA splicing and have been shown to suppress cell growth. Knockdown of CLK2 was found to block glioma stem-like cell (GSC) growth in vivo through the AKT/FOXO3a/p27 pathway without activating mTOR and MAPK signaling, suggesting that these pathways mediate resistance to CLK2 inhibition. We identified CLK2 binding partners using immunoprecipitation assays and confirmed their interactions in vitro in GSCs. We then tested the cellular viability of several signaling inhibitors in parental and CLK2 knockdown GSCs. Our results demonstrate that CLK2 binds to 14-3-3τ isoform and prevents its ubiquitination in GSCs. Stable CLK2 knockdown increased PP2A activity and activated PI3K signaling. Treatment with a PI3K/mTOR inhibitor in CLK2 knockdown cells led to a modest reduction in cell viability compared to drug treatment alone at a lower dose. However, FGFR inhibitor in CLK2 knockdown cells led to a decrease in cell viability and increased apoptosis. Reduced expression of CLK2 in glioblastoma, in combination with FGFR inhibitors, led to synergistic apoptosis induction and cell cycle arrest compared to blockade or either kinase alone.
Recommended Citation
Park S,
Mittal S,
Dong J,
Jeong K,
Martinez-Ledesma E,
Piao Y,
Khan S,
Henry V,
Verhaak R,
Majd N,
Balasubramaniyan V,
de Groot J.
Depletion of CLK2 sensitizes glioma stem-like cells to PI3K/mTOR and FGFR inhibitors. Am J Cancer Res 2020 Nov 1; 10(11):3765-3783