Pérès Elodie A, Gérault Aurélie N, Valable Samuel, Roussel Simon, Toutain Jérôme, Divoux Didier, Guillamo Jean-Sébastien, Sanson Marc, Bernaudin Myriam, Petit Edwige
CNRS, UMR 6301-ISTCT, CERVOxy group. GIP CYCERON, Bd Henri Becquerel, BP5229, F-14074 CAEN, France.
CEA, DSV/I2BM, UMR 6301-ISTCT.
Oncotarget. 2015 Feb 10;6(4):2101-19. doi: 10.18632/oncotarget.2937.
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.
缺氧诱导基因可能导致胶质母细胞瘤（GBM）产生治疗抗性，GBM是最具侵袭性且缺氧的脑肿瘤。最近有报道称，促红细胞生成素（EPO）及其受体（EPOR）参与胶质瘤生长。我们现在研究了EPOR信号传导是否可能调节基于化疗（替莫唑胺，TMZ）和放疗（X射线）的GBM当前治疗的疗效。使用RNA干扰，我们在胶质瘤细胞系（U87和U251）上表明，EPOR沉默会诱导G2/M期细胞周期停滞，这与EPOR基因敲除诱导的胶质瘤生长减缓一致。在体内，我们还报告称，与单独使用TMZ相比，EPOR沉默与TMZ治疗相结合在延迟肿瘤复发和延长动物生存期方面更有效。在体外，我们表明，EPOR沉默不仅增加了胶质瘤细胞对TMZ以及X射线的敏感性，还抵消了缺氧诱导的化学抗性和放射抗性。在接受常规治疗的胶质瘤细胞上沉默EPOR会增强衰老并诱导强大的基因组不稳定性，通过增加多倍体细胞数量和细胞周期蛋白B1表达导致半胱天冬酶依赖性有丝分裂死亡。总体而言，这些数据表明EPOR可能是克服对电离辐射或替莫唑胺治疗抗性的一个有吸引力的靶点。
