Oncotarget

Research Papers:

Silencing erythropoietin receptor on glioma cells reinforces efficacy of temozolomide and X-rays through senescence and mitotic catastrophe

Elodie A. Pérès, Aurélie N. Gérault, Samuel Valable, Simon Roussel, Jérôme Toutain, Didier Divoux, Jean-Sébastien Guillamo, Marc Sanson, Myriam Bernaudin and Edwige Petit _

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Oncotarget. 2015; 6:2101-2119. https://doi.org/10.18632/oncotarget.2937

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Abstract

Elodie A. Pérès1,2,3,4, Aurélie N. Gérault1,2,3,4, Samuel Valable1,2,3,4, Simon Roussel1,2,3,4, Jérôme Toutain1,2,3,4, Didier Divoux1,2,3,4, Jean-Sébastien Guillamo1,2,3,4,5, Marc Sanson6, Myriam Bernaudin1,2,3,4 and Edwige Petit1,2,3,4

1 CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France

2 CEA, DSV/I2BM, UMR 6301-ISTCT

3 Université de Caen Basse-Normandie, UMR 6301-ISTCT

4 Normandie University, France

5 CHU de Caen, Service de Neurologie, Boulevard Côte de Nacre, F-14000 Caen, France

6 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

Correspondence:

Edwige Petit, email:

Keywords: brain tumour, erythropoietin receptor, temozolomide, ionising radiation, senescence, mitotic death

Received: July 21, 2014 Accepted: December 02, 2014 Published: December 03, 2014

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.


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