Titre
CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Xu, Yin
Auteure/Auteur
Stamenkovic, Ivan
Auteure/Auteur
Yu, Qin
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1538-7445[electronic], 0008-5472[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
70
Numéro
6
Première page
2455
Dernière page/numéro d’article
2464
Peer-reviewed
Oui
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.
Sujets
PID Serval
serval:BIB_56431401261A
PMID
Open Access
Oui
Date de création
2010-07-01T14:12:04.608Z
Date de création dans IRIS
2025-05-20T15:04:49Z
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Nom
BIB_56431401261A.P001.pdf
Version du manuscrit
preprint
Taille
4.16 MB
Format
Adobe PDF
PID Serval
serval:BIB_56431401261A.P001
URN
urn:nbn:ch:serval-BIB_56431401261A3
Somme de contrôle
(MD5):019630bb4d31d33864cc12f0c1be7763