title: 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 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.
authors.affiliation: CNRS UMR 7213, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Hana
authors.initials: H
authors.lastname: Janouskova
authors.forename: Anne
authors.initials: A
authors.lastname: Maglott
authors.forename: David Y
authors.initials: DY
authors.lastname: Leger
authors.forename: Catherine
authors.initials: C
authors.lastname: Bossert
authors.forename: Fanny
authors.initials: F
authors.lastname: Noulet
authors.forename: Eric
authors.initials: E
authors.lastname: Guerin
authors.forename: Dominique
authors.initials: D
authors.lastname: Guenot
authors.forename: Sophie
authors.initials: S
authors.lastname: Pinel
authors.forename: Pascal
authors.initials: P
authors.lastname: Chastagner
authors.forename: François
authors.initials: F
authors.lastname: Plenat
authors.forename: Natacha
authors.initials: N
authors.lastname: Entz-Werle
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lehmann-Che
authors.forename: Julien
authors.initials: J
authors.lastname: Godet
authors.forename: Sophie
authors.initials: S
authors.lastname: Martin
authors.forename: Jan
authors.initials: J
authors.lastname: Teisinger
authors.forename: Monique
authors.initials: M
authors.lastname: Dontenwill
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D039081:Integrin alpha5beta1 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D000077204:Temozolomide; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D039081:Integrin alpha5beta1; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D003606:Dacarbazine; D000077204:Temozolomide