Integrin alpha5beta1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high-grade glioma.
Fiche publication
Date publication
juillet 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHASTAGNER Pascal, Dr DONTENWILL Monique, Pr ENTZ-WERLE Natacha, Dr GUENOT Dominique, Dr GUERIN Eric, Dr MARTIN Sophie, Dr PINEL Sophie
Tous les auteurs :
Janouskova H, Maglott A, Leger DY, Bossert C, Noulet F, Guerin E, Guenot D, Pinel S, Chastagner P, Plenat F, Entz-Werle N, Lehmann-Che J, Godet J, Martin S, Teisinger J, Dontenwill M
Lien Pubmed
Résumé
Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the alpha5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the alpha5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of alpha5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the alpha5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, alpha5beta1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high alpha5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between alpha5beta1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that alpha5beta1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of alpha5beta1 integrin.
Référence
Cancer Res. 2012 Jul 15;72(14):3463-70