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Research ArticleArticle

Identification of Survival Genes in Human Glioblastoma Cells by Small Interfering RNA Screening

Nikhil G. Thaker, Fang Zhang, Peter R. McDonald, Tong Ying Shun, Michael D. Lewen, Ian F. Pollack and John S. Lazo
Molecular Pharmacology December 2009, 76 (6) 1246-1255; DOI: https://doi.org/10.1124/mol.109.058024
Nikhil G. Thaker
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Fang Zhang
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Peter R. McDonald
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Tong Ying Shun
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Michael D. Lewen
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Ian F. Pollack
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John S. Lazo
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Abstract

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. Glioblastoma represents a challenging form of cancer for chemotherapy. Therefore, we assayed 16,560 short interfering RNA (siRNA) aimed at identifying which of the 5520 unique therapeutically targetable gene products were important for the survival of human glioblastoma. We analyzed the viability of T98G glioma cells 96 h after siRNA transfection with two orthogonal statistical methods and identified 55 survival genes that encoded proteases, kinases, and transferases. It is noteworthy that 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 nonglioma 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; through either small molecule inhibition or RNA interference, we highlight the potential significance of proteasome inhibition.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant P01-NS40923]; the National Institutes of Health National Cancer Institute [Grant P01-CA78039]; and the Doris Duke Charitable Foundation.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.058024

  • ABBREVIATIONS:

    siRNA
    short interfering RNA
    GBM
    glioblastoma multiforme
    HA
    human astrocyte
    HUVEC
    human umbilical vein endothelial cell
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    PSMB4
    proteasome subunit β
    PARP
    poly (ADP-ribose) polymerase
    PCR
    polymerase chain reaction
    MAD
    median of the absolute deviation
    NF-κB
    nuclear factor κ-light-chain-enhancer of activated B cells
    IPA
    Ingenuity Pathways Analysis.

    • Received May 27, 2009.
    • Accepted September 24, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (6)
Molecular Pharmacology
Vol. 76, Issue 6
1 Dec 2009
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Research ArticleArticle

Identification of Survival Genes in Human Glioblastoma Cells by Small Interfering RNA Screening

Nikhil G. Thaker, Fang Zhang, Peter R. McDonald, Tong Ying Shun, Michael D. Lewen, Ian F. Pollack and John S. Lazo
Molecular Pharmacology December 1, 2009, 76 (6) 1246-1255; DOI: https://doi.org/10.1124/mol.109.058024

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Research ArticleArticle

Identification of Survival Genes in Human Glioblastoma Cells by Small Interfering RNA Screening

Nikhil G. Thaker, Fang Zhang, Peter R. McDonald, Tong Ying Shun, Michael D. Lewen, Ian F. Pollack and John S. Lazo
Molecular Pharmacology December 1, 2009, 76 (6) 1246-1255; DOI: https://doi.org/10.1124/mol.109.058024
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