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.

XRCC2 as a predictive biomarker for radioresistance in locally advanced rectal cancer patients undergoing preoperative radiotherapy

“…Western blotting was performed as previously described [ 49 ]. Briefly, equal amounts of lysates were resolved with SDS-PAGE and were transferred onto PVDF membranes.…”

Hadrontherapy Interactions in Molecular and Cellular Biology

“…The dense and homogeneous distribution of ROS (HO•) following x-rays activates migration/invasion mechanisms, whereas the clustering of ROS around carbon ion trajectories can prevent HIF-1 and upstream signaling [50]. Targeting HIF-1 or its target genes, such as survivin and erythropoietin receptor, could enhance the efficacy of photon RT and carbon RT in several tumor types [23,49,51,52].…”

Imaging Modalities to Assess Oxygen Status in Glioblastoma

“…Moreover, hypoxia greatly impacts therapeutic efficacy. For instance, it is known that the degree of oxygenation is critical for the efficacy of both radiation therapy and chemotherapy ( 5 ). All these aspects are summarized in Figure 1 .…”

“…After selection by markers of hypoxia, the use of radiosensitizers has also been proposed for head and neck cancers (EORCT trail 1219), an approach that could be applied to GBM patients. Our group has also demonstrated that hypoxia-inducible genes, such as erythropoietin, are involved in GBM growth and resistance to treatment ( 5 ). Grounded on hypoxia imaging, such proteins would represent novel and original targets for therapy.…”