Cool-1-mediated inhibition of c-Cbl modulates multiple critical properties of glioblastomas, including the ability to generate tumors in vivo

Brett M. Stevens, Christopher J. Folts, Wanchang Cui, Addie L. Bardin, Kevin Walter, Eleanor Carson-Walter, Angelo Vescovi, Mark Noble

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1124-1135
Number of pages12
JournalStem Cells
Volume32
Issue number5
DOIs
Publication statusPublished - 2014

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Keywords

  • Glioblastoma c-Cbl
  • Redox
  • Redox/Fyn/c-Cbl pathway
  • Tumor initiating cell
  • Tumor initiation

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

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