CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_56431401261A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.
Périodique
Cancer Research
Auteur(s)
Xu Yin, Stamenkovic Ivan, Yu Qin
ISSN
1538-7445[electronic], 0008-5472[linking]
Statut éditorial
Publié
Date de publication
2010
Peer-reviewed
Oui
Volume
70
Numéro
6
Pages
2455-2464
Langue
anglais
Résumé
Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemotherapy and radiotherapy, is currently incurable. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize glioblastoma cells to cytotoxic drugs is therefore urgently needed. CD44 is a major cell surface hyaluronan receptor and cancer stem cell marker that has been implicated in the progression of a variety of cancer types. However, the major downstream signaling pathways that mediate its protumor effects and the role of CD44 in the progression and chemoresponse of GBM have not been established. Here we show that CD44 is upregulated in GBM and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. Consistent with this observation, CD44 antagonists potently inhibit glioma growth in preclinical mouse models. We provide the first evidence that CD44 functions upstream of the mammalian Hippo signaling pathway and that CD44 promotes tumor cell resistance to reactive oxygen species-induced and cytotoxic agent-induced stress by attenuating activation of the Hippo signaling pathway. Together, our results identify CD44 as a prime therapeutic target for GBM, establish potent antiglioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how upregulation of CD44 may constitute a key event in leading to cancer cell resistance to stresses of different origins. Finally, our results provide a rational explanation for the observation that functional inhibition of CD44 augments the efficacy of chemotherapy and radiation therapy.
Mots-clé
Animals, Antigens, CD44/biosynthesis, Antigens, CD44/genetics, Apoptosis/physiology, Brain Neoplasms/drug therapy, Brain Neoplasms/genetics, COS Cells, Cell Growth Processes/physiology, Cercopithecus aethiops, Glioblastoma/drug therapy, Glioblastoma/genetics, Humans, Immunoglobulin Fc Fragments/genetics, Immunoglobulin Fc Fragments/pharmacology, Mice, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins c-met/metabolism, RNA, Small Interfering/genetics, Recombinant Fusion Proteins/genetics, Recombinant Fusion Proteins/isolation & purification, Signal Transduction, Up-Regulation
Pubmed
Web of science
Open Access
Oui
Création de la notice
01/07/2010 16:12
Dernière modification de la notice
20/08/2019 15:10
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