Cool-1-Mediated Inhibition of c-Cbl Modulates Multiple Critical Properties of Glioblastomas, Including the Ability to Generate Tumors In Vivo

Authors

  • Brett M. Stevens,

    1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA
    Current affiliation:
    1. Current address: Brett M. Stevens, Ph.D., University of Colorado Anschutz Medical Campus Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation 12700 E 19th Avenue Rm 9122 RC2, MS B170 Aurora CO 80045
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  • Christopher J. Folts,

    1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA
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  • Wanchang Cui,

    1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA
    2. Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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  • Addie L. Bardin,

    1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA
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  • Kevin Walter,

    1. Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA
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  • Eleanor Carson-Walter,

    1. Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA
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  • Angelo Vescovi,

    1. Department of Biotechnology and Biosciences, University of Milano-Bicocca and StemGen SpA, Milan, Italy
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  • Mark Noble

    Corresponding author
    1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA
    • Correspondence: Mark Noble, Ph.D., University of Rochester Medical Center, 601 Elmwood Avenue, Box 633, Rochester, New York 14642, USA. Telephone: +1-585 273-1448; Fax: +1-585 273-1450; e-mail: Mark_noble@urmc.rochester.edu

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Abstract

We discovered that glioblastoma (GBM) cells use Cool-1/β-pix to inhibit normal activation of the c-Cbl ubiquitin ligase via the redox/Fyn/c-Cbl pathway and that c-Cbl inhibition is critical for GBM cell function. Restoring normal c-Cbl activity by Cool-1 knockdown in vitro reduced GBM cell division, almost eliminated generation of adhesion-independent spheroids, reduced the representation of cells expressing antigens thought to identify tumor initiating cells (TICs), reduced levels of several proteins of critical importance in TIC function (such as Notch-1 and Sox2), and increased sensitivity to BCNU (carmustine) and temozolomide (TMZ). In vivo, Cool-1 knockdown greatly suppressed the ability of GBM cells to generate tumors, an outcome that was c-Cbl dependent. In contrast, Cool-1 knockdown did not reduce division or increase BCNU or TMZ sensitivity in primary glial progenitor cells and Cool-1/c-Cbl complexes were not found in normal brain tissue. Our studies provide the first evidence that Cool-1 may be critical in the biology of human tumors, that suppression of c-Cbl by Cool-1 may be critical for generation of at least a subset of GBMs and offer a novel target that appears to be selectively necessary for TIC function and modulates chemoresistance in GBM cells. Targeting such proteins that inhibit c-Cbl offers potentially attractive opportunities for therapeutic development. Stem Cells 2014;32:1124–1135

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