期刊
ONCOTARGET
卷 7, 期 38, 页码 62194-62207出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11552
关键词
alpha 5 beta 1 integrin; beta-catenin; migration; EMT; glioma
资金
- University of Strasbourg
- Ligue Contre le Cancer (CCIR Grand Est)
- Fondation ARC pour la Recherche sur le Cancer
- Canceropole Grand Est
- Region Alsace
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 alpha 5 beta 1 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 alpha 5 beta 1 integrin and beta-catenin activation in glioma cells. We demonstrated that overexpression and activation by fibronectin of alpha 5 beta 1 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 alpha 5 beta 1 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 alpha 5 beta 1 integrin/AKT axis in glioma cell resistance to therapies and migration each supported by different signaling pathways. Our data thus suggest that alpha 5 beta 1 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.
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