Integrin α5β1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high-grade glioma. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2012

Integrin α5β1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high-grade glioma.

Jan Teisinger
  • Fonction : Auteur

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 α5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the α5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of α5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the α5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, α5β1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high α5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between α5β1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that α5β1 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 α5β1 integrin.

Domaines

Cancer

Dates et versions

hal-00746868 , version 1 (29-10-2012)

Identifiants

Citer

Hana Janouskova, Anne Maglott, David y Leger, Catherine Bossert, Fanny Noulet, et al.. Integrin α5β1 plays a critical role in resistance to temozolomide by interfering with the p53 pathway in high-grade glioma.. Cancer Research, 2012, 72 (14), pp.3463-3470. ⟨10.1158/0008-5472.CAN-11-4199⟩. ⟨hal-00746868⟩
463 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More