title: Silencing erythropoietin receptor on glioma cells reinforces efficacy of temozolomide and X-rays through senescence and mitotic catastrophe.
abstract: Hypoxia-inducible genes may contribute to therapy resistance in glioblastoma (GBM), the most aggressive and hypoxic brain tumours. It has been recently reported that erythropoietin (EPO) and its receptor (EPOR) are involved in glioma growth. We now investigated whether EPOR signalling may modulate the efficacy of the GBM current treatment based on chemotherapy (temozolomide, TMZ) and radiotherapy (X-rays). Using RNA interference, we showed on glioma cell lines (U87 and U251) that EPOR silencing induces a G2/M cell cycle arrest, consistent with the slowdown of glioma growth induced by EPOR knock-down. In vivo, we also reported that EPOR silencing combined with TMZ treatment is more efficient to delay tumour recurrence and to prolong animal survival compared to TMZ alone. In vitro, we showed that EPOR silencing not only increases the sensitivity of glioma cells to TMZ as well as X-rays but also counteracts the hypoxia-induced chemo- and radioresistance. Silencing EPOR on glioma cells exposed to conventional treatments enhances senescence and induces a robust genomic instability that leads to caspase-dependent mitotic death by increasing the number of polyploid cells and cyclin B1 expression. Overall these data suggest that EPOR could be an attractive target to overcome therapeutic resistance toward ionising radiation or temozolomide.
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Elodie A
authors.initials: EA
authors.lastname: Pérès
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Aurélie N
authors.initials: AN
authors.lastname: Gérault
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Valable
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Roussel
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Toutain
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Divoux
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.|CHU de Caen, Service de Neurologie, Boulevard Côte de Nacre, F-14000 Caen, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Guillamo
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moëlle épinière (CRICM), UMR-S975, F-75013 Paris, France; INSERM, U 975, F-75013 Paris, France; CNRS, UMR 7225, F-75013 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Bernaudin
authors.affiliation: CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.|CEA, DSV/I2BM, UMR 6301-ISTCT.|Université de Caen Basse-Normandie, UMR 6301-ISTCT.|Normandie University, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Petit
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D056744:Cyclin B1 / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D011123:Polyploidy; D034622:RNA Interference; D000067492:RNAi Therapeutics; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D056744:Cyclin B1; D017467:Receptors, Erythropoietin; D003606:Dacarbazine; D000077204:Temozolomide