Alphavbeta3 and alphavbeta5 integrins control glioma cell response to ionising radiation through ILK and RhoB.
Integrins are extracellular matrix receptors involved in tumour invasion and angiogenesis. Although there is evidence that inhibiting integrins might enhance the efficiency of radiotherapy, little is known about the exact mechanisms involved in the integrin-dependent modulation of tumor radiosensitivity. The purpose of this study was to investigate the role of alphavbeta3 and alphavbeta5 integrins in glioblastoma cell radioresistance and overall to decipher the downstream biological pathways. We first demonstrated that silencing alphavbeta3 and alphavbeta5 integrins with specific siRNAs significantly reduced the survival after irradiation of 2 glioblastoma cell lines: U87 and SF763. We then showed that integrin activity and integrin signalling pathways controlled the glioma cell radiosensitivity. This regulation of glioma cell response to ionising radiation was mediated through the integrin-linked kinase, ILK, and the small GTPase, RhoB, by two mechanisms. The first one, independent of ILK, consists in the regulation of the intracellular level of RhoB by alphavbeta3 or alphavbeta5 integrin. The second pathway involved in cell radiosensitivity consists in RhoB activation by ionising radiation through ILK. Furthermore, we demonstrated that the alphavbeta3/alphavbeta5 integrins/ILK/RhoB pathway controlled the glioma cells radiosensitivity by regulating radiation-induced mitotic cell death. This work identifies a new biological pathway controlling glioblastoma cells radioresistance, activated from the membrane through alphavbeta3 and/or alphavbeta5 integrins via ILK and RhoB. Our results are clues that downstream effectors of alphavbeta3 and alphavbeta5 integrins as ILK and RhoB might also be promising candidate targets for improving the efficiency of radiotherapy and thus the clinical outcome of patients with glioblastoma.
Monferran
Sylvie
S
Institut Claudius Regaud, INSERMU563, Department of Oncogenesis, Signalling and Therapeutic Innovation, France.
Skuli
Nicolas
N
Institut Claudius Regaud, INSERMU563, Department of Oncogenesis, Signalling and Therapeutic Innovation, France.
Delmas
Caroline
C
Institut Claudius Regaud, INSERMU563, Department of Oncogenesis, Signalling and Therapeutic Innovation, France.
Favre
Gilles
G
Institut Claudius Regaud, INSERMU563, Department of Oncogenesis, Signalling and Therapeutic Innovation, France.
Bonnet
Jacques
J
Department of Radiations, 20-24 rue du Pont St Pierre, 31052 Toulouse, France.
Cohen-Jonathan-Moyal
Elizabeth
E
Institut Claudius Regaud, INSERMU563, Department of Oncogenesis, Signalling and Therapeutic Innovation, France.|Department of Radiations, 20-24 rue du Pont St Pierre, 31052 Toulouse, France.
Toulas
Christine
C
Institut Claudius Regaud, INSERMU563, Department of Oncogenesis, Signalling and Therapeutic Innovation, France.
D045744:Cell Line, Tumor / Q000528:radiation effects; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism / Q000532:radiotherapy; D005910:Glioma / Q000378:metabolism* / Q000532:radiotherapy*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D019030:Receptors, Vitronectin / Q000378:metabolism*; D014162:Transfection; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D039302:Integrin alphaVbeta3; D016023:Integrins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D019030:Receptors, Vitronectin; D020743:rhoB GTP-Binding Protein; D000099200:Scaffold Protein ILK; C064660:integrin alphaVbeta5