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

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 a5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the a5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of a5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the a5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, a5b1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high a5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between a5b1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that a5b1 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 a5b1 integrin. Cancer Res; 72(14); 3463-70. Ó2012 AACR.

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

“…We reasoned that PEA-15 may be one of the links between α5β1 integrin and p53 pathways. Interestingly, similarly to the depletion of α5 integrin, 8 depletion of PEA-15 in U87MG-α5 high cells stabilized and activated p53 (Figure 5a). Addition of Nutlin-3a to siPEA-15 cells significantly enhanced the p53 expression/ phosphorylation compared with control si-nt cells (Figure 5a).…”

“…We demonstrated that α5β1 integrin interferes with the p53 pathway and that Nutlin-3a (10 μM) represses the α5 integrin subunit through the activation of p53. 8,24 We wondered whether α5 integrin repression would sensitize glioma cells to Nutlin-3a. We treated U87MG cells overexpressing (U87MG-α5 high) or repressed (U87MG-α5 low) for α5 integrin with different doses of Nutlin-3a and evaluated their clonogenic potential.…”

“…4 In tumor cells, integrins impact on proliferation/survival, therapy resistances and tumor recurrence. α5β1 integrin has emerged recently and has been shown to participate in aggressiveness of solid tumors [5][6][7][8][9] as reviewed in Schaffner et al 10 High expression of α5 integrin is associated with a decrease in patient overall survival, making α5β1 integrin an important factor in resistance to therapies. Numerous preclinical data support the ability of integrin antagonists to disrupt integrin signaling pathways leading to inhibition of angiogenesis and/or tumor growth but also to sensitization toward therapies.…”

“…We characterized a negative crosstalk between α5β1 integrin and p53wt implicated in temozolomide (TMZ) resistance. 8 Antagonists of α5β1 integrin pushed TMZ-treated cells from senescence toward apoptosis while modulating the p53 pathway. 24 Nutlin-3a, by inhibiting p53-HDM2 interaction, induced a huge increase in p53 activity but also decreased the expression level of α5 integrin in p53wt GBM or colon cancer cells.…”

“…24 Nutlin-3a, by inhibiting p53-HDM2 interaction, induced a huge increase in p53 activity but also decreased the expression level of α5 integrin in p53wt GBM or colon cancer cells. 8,26 Here, we investigated the potential benefit of targeting GBM with antagonists of α5β1 integrin and Nutlin-3a. We demonstrated the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin, in the apoptotic outcome of this dual targeting therapy.…”