Expression/activation of α5β1 integrin is linked to the β-catenin signaling pathway to drive migration in glioma cells

• Published in: Oncotarget Vol. 7; no. 38; pp. 62194 - 62207
• Main Authors: Renner, Guillaume, Noulet, Fanny, Mercier, Marie-Cécile, Choulier, Laurence, Etienne-Selloum, Nelly, Gies, Jean-Pierre, Lehmann, Maxime, Lelong-Rebel, Isabelle, Martin, Sophie, Dontenwill, Monique
• Format: Journal Article
• Language: English
• Published: United States Impact journals 20.09.2016; Impact Journals LLC
• Subjects: Apoptosis; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition - drug effects; Fibronectins - metabolism; Glioma - genetics; Glioma - pathology; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Immunohistochemistry; Integrin alpha5beta1 - antagonists & inhibitors; Integrin alpha5beta1 - metabolism; Life Sciences; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Tankyrases - antagonists & inhibitors; Transcriptional Activation - drug effects; Wnt Signaling Pathway; beta-catenin; migration; glioma; α5β1 integrin; EMT
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.11552

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.