title: Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma.
abstract: 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.
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: G
authors.initials: G
authors.lastname: Renner
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: H
authors.initials: H
authors.lastname: Janouskova
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: F
authors.initials: F
authors.lastname: Noulet
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: V
authors.initials: V
authors.lastname: Koenig
authors.affiliation: EA3430, Université de Strasbourg, Strasbourg, France.
authors.forename: E
authors.initials: E
authors.lastname: Guerin
authors.affiliation: Tumor Virology Division (F010), Deutsches Krebsforschungszentrum/German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bär
authors.affiliation: Tumor Virology Division (F010), Deutsches Krebsforschungszentrum/German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Nuesch
authors.affiliation: Department Chemie, Institute for Advanced Study and Center of Integrated Protein Studies, Technische Universität München, Garching, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Rechenmacher
authors.affiliation: Department Chemie, Institute for Advanced Study and Center of Integrated Protein Studies, Technische Universität München, Garching, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Neubauer
authors.affiliation: Department Chemie, Institute for Advanced Study and Center of Integrated Protein Studies, Technische Universität München, Garching, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kessler
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: A-F
authors.initials: AF
authors.lastname: Blandin
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: L
authors.initials: L
authors.lastname: Choulier
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: N
authors.initials: N
authors.lastname: Etienne-Selloum
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: M
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: I
authors.initials: I
authors.lastname: Lelong-Rebel
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: S
authors.initials: S
authors.lastname: Martin
authors.affiliation: Integrins and Cancer, Faculté de Pharmacie, UMR7213 CNRS, LBP, Tumoral Signaling and Therapeutic Targets Department, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: M
authors.initials: M
authors.lastname: Dontenwill
mesh_terms: D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D039081:Integrin alpha5beta1; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53