Integrin α5β1 expression is correlated with a worse prognosis in high-grade
glioma. We previously unraveled a negative crosstalk between
integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of
glioblastoma to
chemotherapies. The restoration of p53
tumor-suppressor function is under intensive investigations for
cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as
Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether
integrin α5β1 functional inhibition or repression could sensitize
glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1
integrin-specific
blocking antibodies or small RGD-like antagonists in association with
Nutlin-3a triggered a
caspase (Casp) 8/Casp 3-dependent strong apoptosis in
glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two
anti-apoptotic proteins,
phosphoprotein enriched in astrocytes 15 (PEA-15) and
survivin in
glioma cell apoptotic outcome. PEA-15 is under α5β1
integrin/AKT (
protein kinase B) control and
survivin is a p53-repressed target. Moreover, interconnections between
integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific
small-interfering RNA (
siRNA)-activated p53 pathway to repress
survivin and conversely
survivin repression by specific
siRNA decreased α5β1
integrin expression. This pro-apoptotic loop could be generalized to several
glioma cell lines, whatever their p53 status, inasmuch PEA-15 and
survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1
integrin and activation of p53 modulates two
anti-apoptotic proteins crucially involved in the apoptotic answer of
glioma cells. Importantly, our results suggest that high-grade
glioma expressing high level of α5β1
integrin may benefit from associated
therapies including
integrin antagonists and repressors of
survivin expression.