Integrin α5β1 Plays a Critical Role in Resistance to Temozolomide by Interfering with the p53 Pathway in High-Grade Glioma

Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the alpha 5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the alpha 5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of alpha 5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the alpha 5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, alpha 5 beta 1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high alpha 5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between alpha 5 beta 1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that alpha 5 beta 1 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 alpha 5 beta 1 integrin. Cancer Res; 72(14); 3463-70. (C)2012 AACR.