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

• Published in: Cell death and differentiation Vol. 23; no. 4; pp. 640 - 653
• Main Authors: Renner, G, Janouskova, H, Noulet, F, Koenig, V, Guerin, E, Bär, S, Nuesch, J, Rechenmacher, F, Neubauer, S, Kessler, H, Blandin, A-F, Choulier, L, Etienne-Selloum, N, Lehmann, M, Lelong-Rebel, I, Martin, S, Dontenwill, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2016; Nature Publishing Group
• Subjects: 13; 13/2; 13/95; 631/67/581; 96; Apoptosis; Apoptosis - genetics; Astrocytes - metabolism; Astrocytes - pathology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Line, Tumor; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Humans; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Integrin alpha5beta1 - genetics; Integrin alpha5beta1 - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Original Paper; Phosphoproteins - genetics; Phosphoproteins - metabolism; Signal Transduction; Stem Cells; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2015.131

Integrin α 5 β 1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α 5 β 1 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 α 5 β 1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α 5 β 1 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 α 5 β 1 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 α 5 β 1 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 α 5 β 1 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 α 5 β 1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.