TY - JOUR
T1 - Cool-1-mediated inhibition of c-Cbl modulates multiple critical properties of glioblastomas, including the ability to generate tumors in vivo
AU - Stevens, Brett M.
AU - Folts, Christopher J.
AU - Cui, Wanchang
AU - Bardin, Addie L.
AU - Walter, Kevin
AU - Carson-Walter, Eleanor
AU - Vescovi, Angelo
AU - Noble, Mark
N1 - Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
KW - Glioblastoma c-Cbl
KW - Redox
KW - Redox/Fyn/c-Cbl pathway
KW - Tumor initiating cell
KW - Tumor initiation
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U2 - 10.1002/stem.1644
DO - 10.1002/stem.1644
M3 - Article
C2 - 24458840
AN - SCOPUS:84898933319
VL - 32
SP - 1124
EP - 1135
JO - STEM CELLS
JF - STEM CELLS
SN - 1066-5099
IS - 5
ER -