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

Hana Janouskova,François Plenat,Eric Guerin,Natacha Entz-Werle,Jan Teisinger,Dominique Guenot,Jacqueline Lehmann-Che,Fanny Noulet,Sophie Pinel,Sophie Martin,Pascal Chastagner,Catherine Bossert,Monique Dontenwill,David Y Leger,Julien Godet,Anne Maglott

doi:10.1158/0008-5472.can-11-4199

Hana Janouskova, François Plenat + Show 14 more

Open Access

https://doi.org/10.1158/0008-5472.can-11-4199

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Abstract

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.

Highlights

Glioblastoma multiforme (GBM) are the most aggressive brain tumors and remain a challenge for oncologists
Through the use of non-peptidic a5b1 integrin antagonists and GBM cell lines, we previously showed that a5b1 integrin may be a therapeutic target for these tumors [8, 9] and that concomitant addition of a5b1 antagonists sensitizes p53 wild-type (p53-wt) glioma cells to chemotherapeutic drugs [10]
In agreement with our data, it was reported that the a5b1 integrin is overexpressed at the protein level in a significant proportion of human glioblastoma biopsies [20]

Summary

Introduction

Glioblastoma multiforme (GBM) are the most aggressive brain tumors and remain a challenge for oncologists. Gene expression profiling of high-grade glioma revealed that genes of extracellular matrix components and their regulators are often affected in the patients. Fibronectin is overexpressed in glioblastoma versus normal brain [1] and belongs to the cluster of genes associated with a more malignant phenotype [2, 3]. It has recently been shown that fibronectin knockdown delays tumor growth in a mouse glioma model [4]. The a5b1 integrin is a fibronectin receptor that was recently shown to have an important role in tumor progression [5], metastasis [6], and/or resistance to therapies [7] in lung, ovarian, and breast cancer, respectively

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