RT Journal Article
SR Electronic
T1 Identification of Survival Genes in Human Glioblastoma Cells Using siRNA Screening
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.058024
DO 10.1124/mol.109.058024
A1 Thaker, Nikhil G
A1 Zhang, Fang
A1 McDonald, Peter R.
A1 Shun, Tong Ying
A1 Lewen, Michael D
A1 Pollack, Ian F.
A1 Lazo, John S.
YR 2009
UL http://molpharm.aspetjournals.org/content/early/2009/09/28/mol.109.058024.abstract
AB Target identification and validation remain difficult steps in the drug discovery process, and uncovering the core genes and pathways that are fundamental for cancer cell survival may facilitate this process. Therefore, we implemented a short interfering RNA (siRNA) screen with 16,560 siRNAs targeting 5,520 unique druggable human genes aimed at identifying these survival genes in the T98G glioma cell line because glioblastoma represents a challenging form of cancer for chemotherapy. We analyzed cell viability at 96 hr after siRNA transfection with two orthogonal statistical methods and identified 55 survival genes that encoded proteases, kinases, and transferases. Interestingly, 22% (12/55) of the survival genes were constituents of the 20S and 26S proteasome subunits. An expression survey of a panel of glioma cell lines demonstrated expression of the proteasome component PSMB4, and the validity of the proteasome complex as a target for survival inhibition was confirmed in a series of glioma and non-glioma cell lines by pharmacological inhibition and RNA interference. Biological networks were built with the other survival genes using a protein-protein interaction network, which identified clusters of cellular processes, including protein ubiquitination, purine and pyrimidine metabolism, nucleotide excision repair, and NF-κB signaling. The results of this study should broaden our understanding of the core genes and pathways that regulate cell survival, and we highlight the potential significance of proteasome inhibition, through either small molecule inhibition or RNA interference.The American Society for Pharmacology and Experimental Therapeutics