A radiosensitizing effect of RAD51 inhibition in glioblastoma stem-like cells.

Anaïs Balbous,Baptiste Pinel,René Jean Bensadoun,Michel Wager,Lucie Karayan-Tapon,Ulrich Cortes,Mathilde Duchesne,Jean-Claude Chomel,Karline Guilloteau,Odile Boissonnade,Pierre Rivet,Julie Godet

doi:10.1186/s12885-016-2647-9

Anaïs Balbous, Baptiste Pinel + Show 10 more

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https://doi.org/10.1186/s12885-016-2647-9

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Abstract

BackgroundRadioresistant glioblastoma stem cells (GSCs) contribute to tumor recurrence and identification of the molecular targets involved in radioresistance mechanisms is likely to enhance therapeutic efficacy. This study analyzed the DNA damage response following ionizing radiation (IR) in 10 GSC lines derived from patients.MethodsDNA damage was quantified by Comet assay and DNA repair effectors were assessed by Low Density Array. The effect of RAD51 inhibitor, RI-1, was evaluated by comet and annexin V assays.ResultsWhile all GSC lines displayed efficient DNA repair machinery following ionizing radiation, our results demonstrated heterogeneous responses within two distinct groups showing different intrinsic radioresistance, up to 4Gy for group 1 and up to 8Gy for group 2. Radioresistant cell group 2 (comprising 5 out of 10 GSCs) showed significantly higher RAD51 expression after IR. In these cells, inhibition of RAD51 prevented DNA repair up to 180 min after IR and induced apoptosis. In addition, RAD51 protein expression in glioblastoma seems to be associated with poor progression-free survival.ConclusionThese results underscore the importance of RAD51 in radioresistance of GSCs. RAD51 inhibition could be a therapeutic strategy helping to treat a significant number of glioblastoma, in combination with radiotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2647-9) contains supplementary material, which is available to authorized users.

Highlights

Radioresistant glioblastoma stem cells (GSCs) contribute to tumor recurrence and identification of the molecular targets involved in radioresistance mechanisms is likely to enhance therapeutic efficacy
DNA repair kinetics following ionizing radiation (IR) exposure in glioblastoma stem cells To investigate the kinetics of DNA repair in glioblastoma stem cells after IR, we conducted a study on a series of 10 GSCs
Cells were exposed to 4Gy IR and DNA damage was monitored by single-cell gel electrophoresis or “comet assay” in alkaline conditions so as to simultaneously detect both double and single-strand DNA breaks with high sensitivity [22]

Summary

Introduction

Radioresistant glioblastoma stem cells (GSCs) contribute to tumor recurrence and identification of the molecular targets involved in radioresistance mechanisms is likely to enhance therapeutic efficacy. GBM are resistant to current treatment with recurrence patterns and a median survival of 14.6 months [1] It is well-established that GBM are composed of heterogeneous tumor cell populations, including tumor cells with characteristics similar to neural progenitor cells called “glioblastoma stem cells” (GSCs) [2, 3]. Accumulating evidence indicate that GSCs can survive DNA damage and are able to repopulate the tumor after treatment [4, 5] contributing to radioresistance and tumor recurrence. Unlike neural progenitor cells using the NHEJ pathway, GSCs preferentially activate the HR pathway to repair DNA damage [8, 17, 18]

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