TY - JOUR
T1 - CRMP5 controls glioblastoma cell proliferation and survival through Notch-dependent signaling
AU - Moutal, Aubin
AU - Honnorat, Jérôme
AU - Massoma, Patrick
AU - Désormeaux, Pauline
AU - Bertrand, Caroline
AU - Malleval, Céline
AU - Watrin, Chantal
AU - Chounlamountri, Naura
AU - Mayeur, Marie Eve
AU - Besançon, Roger
AU - Naudet, Nicolas
AU - Magadoux, Léa
AU - Khanna, Rajesh
AU - Ducray, François
AU - Meyronet, David
AU - Thomasset, Nicole
N1 - Publisher Copyright:
© 2015 AACR.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that play a major role in nervous system development. This protein was first described in cancerinduced autoimmune processes, causing neurodegenerative disorders (paraneoplastic neurologic syndromes). CRMP5 expression has been reported to serve as a biomarker for high-grade lung neuroendocrine carcinomas; however, its functional roles have not been examined in any setting of cancer pathophysiology. In this study, we report two different CRMP5 expression patterns observed in human glioblastoma (GBM) biopsies that establish connections between CRMP5 expression, Notch receptor signaling, and GBM cell proliferation. We demonstrated that elevated CRMP5promotes Notch receptor expression and Akt activation in human tumor cell lines, GBM stem cells, and primary tumor biopsies. We have shown that the high CRMP5 and Notch expression in GBM xenograft is related to stem cells. This suggests that high CRMP5 expression pattern in GBM biopsies encompasses a subset of stem cells. Mechanistically, CRMP5 functioned by hijacking Notch receptors from Itch-dependent lysosomal degradation. Our findings suggest that CRMP5 serves as a major mediator of Notch signaling and Akt activation by controlling the degradation of the Notch receptor, with implications for defining a biomarker signature in GBM that correlates with and may predict patient survival.
AB - Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that play a major role in nervous system development. This protein was first described in cancerinduced autoimmune processes, causing neurodegenerative disorders (paraneoplastic neurologic syndromes). CRMP5 expression has been reported to serve as a biomarker for high-grade lung neuroendocrine carcinomas; however, its functional roles have not been examined in any setting of cancer pathophysiology. In this study, we report two different CRMP5 expression patterns observed in human glioblastoma (GBM) biopsies that establish connections between CRMP5 expression, Notch receptor signaling, and GBM cell proliferation. We demonstrated that elevated CRMP5promotes Notch receptor expression and Akt activation in human tumor cell lines, GBM stem cells, and primary tumor biopsies. We have shown that the high CRMP5 and Notch expression in GBM xenograft is related to stem cells. This suggests that high CRMP5 expression pattern in GBM biopsies encompasses a subset of stem cells. Mechanistically, CRMP5 functioned by hijacking Notch receptors from Itch-dependent lysosomal degradation. Our findings suggest that CRMP5 serves as a major mediator of Notch signaling and Akt activation by controlling the degradation of the Notch receptor, with implications for defining a biomarker signature in GBM that correlates with and may predict patient survival.
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U2 - 10.1158/0008-5472.CAN-14-0631
DO - 10.1158/0008-5472.CAN-14-0631
M3 - Article
C2 - 26122847
AN - SCOPUS:84942861700
SN - 0008-5472
VL - 75
SP - 3519
EP - 3528
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -