Abstract
SummaryPatients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs.
Highlights
It has been widely postulated that a specific sub-population of glioblastoma (GBM) cells exhibit stem-like properties and that they underlie treatment resistance and recurrence due to their ability to survive DNA-damaging treatments and repopulate the tumor (Mannino and Chalmers, 2011)
We reported that targeting RAD51 using small interfering RNA-radiosensitized established glioma cell lines, and recent data confirm that targeting homologous repair (HR) is more effective at radiosensitizing glioblastoma stem cells (GSCs) than inhibiting the major alternative double-strand break (DSB) repair pathway, non-homologous end-joining (NHEJ) (Lim et al, 2014; Short et al, 2011)
RAD51 Is Highly Expressed in GSCs To confirm that RAD51 is a relevant target in GSCs, expression was examined in patient-derived GSCs and normal human astrocytes (NHAs)
Summary
It has been widely postulated that a specific sub-population of glioblastoma (GBM) cells exhibit stem-like properties and that they underlie treatment resistance and recurrence due to their ability to survive DNA-damaging treatments and repopulate the tumor (Mannino and Chalmers, 2011) This population is dynamic and can be altered by specific growth conditions, including exposure to serum and bone morphogenic proteins (BMP), which render them non-tumorigenic (Piccirillo et al, 2006). Upregulated DNA damage responses (DDRs) have been documented in glioblastoma stem cells (GSCs) including enhanced checkpoint signaling and recruitment of repair proteins (Bao et al, 2006; Cheng et al, 2011; Facchino et al, 2010; Zeppernick et al, 2008); the mechanisms underlying resistance to treatment are not fully understood It is not clear how specific resistance mechanisms align with the established phenotypic characteristics that drive recurrence or with marker positivity. It remains unclear which repair pathways are the most relevant targets in GSCs
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