Expression/activation of α5β1 integrin is linked to the β-catenin signaling pathway to drive migration in glioma cells.
The Wnt/beta catenin pathway has been highlighted as an important player of brain tumors aggressiveness and resistance to therapies. Increasing knowledges of the regulation of beta-catenin transactivation point out its hub position in different pathophysiological outcomes in glioma such as survival and migration. Crosstalks between integrins and beta-catenin pathways have been suggested in several tumor tissues. As we demonstrated earlier that α5β1 integrin may be considered as a therapeutic target in high grade glioma through its contribution to glioma cell migration and resistance to chemotherapy, we addressed here the potential relationship between α5β1 integrin and beta-catenin activation in glioma cells. We demonstrated that overexpression and activation by fibronectin of α5β1 integrin allowed the transactivation of beta-catenin gene targets included in an EMT-like program that induced an increase in cell migration. Hampering of beta catenin activation and cell migration could be similarly achieved by a specific integrin antagonist. In addition we showed that α5β1 integrin/AKT axis is mainly involved in these processes. However, blockade of beta-catenin by XAV939 (tankyrase inhibitor leading to beta-catenin degradation) did not synergize with p53 activation aiming to cell apoptosis as was the case with integrin antagonists. We therefore propose a dual implication of α5β1 integrin/AKT axis in glioma cell resistance to therapies and migration each supported by different signaling pathways. Our data thus suggest that α5β1 integrin may be added to the growing list of beta-catenin modulators and provide new evidences to assign this integrin as a valuable target to fight high grade glioma.
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Guillaume
G
Renner
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Fanny
F
Noulet
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Marie-Cécile
MC
Mercier
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Laurence
L
Choulier
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Nelly
N
Etienne-Selloum
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Jean-Pierre
JP
Gies
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Maxime
M
Lehmann
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Isabelle
I
Lelong-Rebel
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Sophie
S
Martin
UMR7213 CNRS, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Monique
M
Dontenwill
D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038501:Tankyrases / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation / Q000187:drug effects; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D005353:Fibronectins; D006575:Heterocyclic Compounds, 3-Ring; D039081:Integrin alpha5beta1; D051057:Proto-Oncogene Proteins c-akt; D038501:Tankyrases; D051176:beta Catenin; C495270:CTNNB1 protein, human; C544261:XAV939; C418109:TNKS protein, human
EMT; beta-catenin; glioma; migration; α5β1 integrin