title: Radiation-induced mitotic cell death and glioblastoma radioresistance: a new regulating pathway controlled by integrin-linked kinase, hypoxia-inducible factor 1 alpha and survivin in U87 cells.
abstract: We have previously shown that integrin-linked kinase (ILK) regulates U87 glioblastoma cell radioresistance by modulating the main radiation-induced cell death mechanism in solid tumours, the mitotic cell death. To decipher the biological pathways involved in these mechanisms, we constructed a U87 glioblastoma cell model expressing an inducible shRNA directed against ILK (U87shILK). We then demonstrated that silencing ILK enhanced radiation-induced centrosome overduplication, leading to radiation-induced mitotic cell death. In this model, ionising radiations induce hypoxia-inducible factor 1 alpha (HIF-1α) stabilisation which is inhibited by silencing ILK. Moreover, silencing HIF-1α in U87 cells reduced the surviving fraction after 2 Gy irradiation by increasing cell sensitivity to radiation-induced mitotic cell death and centrosome amplification. Because it is known that HIF-1α controls survivin expression, we then looked at the ILK silencing effect on survivin expression. We show that survivin expression is decreased in U87shILK cells. Furthermore, treating U87 cells with the specific survivin suppressor YM155 significantly increased the percentage of giant multinucleated cells, centrosomal overduplication and thus U87 cell radiosensitivity. In consequence, we decipher here a new pathway of glioma radioresistance via the regulation of radiation-induced centrosome duplication and therefore mitotic cell death by ILK, HIF-1α and survivin. This work identifies new targets in glioblastoma with the intention of radiosensitising these highly radioresistant tumours.
authors.affiliation: Institut National de Santé et de Recherche Médicale (INSERM), UMR 1037, Cancer Research Center of Toulouse, Toulouse F-31000, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Lanvin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monferran
authors.forename: Caroline
authors.initials: C
authors.lastname: Delmas
authors.forename: Bettina
authors.initials: B
authors.lastname: Couderc
authors.forename: Christine
authors.initials: C
authors.lastname: Toulas
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cohen-Jonathan-Moyal
mesh_terms: D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D018385:Centrosome / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008938:Mitosis / Q000528:radiation effects*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D000077022:Survivin; D013997:Time Factors; D014162:Transfection; D000099200:Scaffold Protein ILK
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D000077022:Survivin; D000099200:Scaffold Protein ILK; C107489:BIRC5 protein, human; C497442:HIF1A protein, human
keywords: Centrosome duplication; Glioblastoma; Hypoxia-inducible factor 1alpha; Integrin-linked kinase; Ionising radiations; Mitotic cell death; Survivin