Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment

被引:7
作者
Lozinski, Mathew [1 ,2 ,3 ]
Bowden, Nikola A. [2 ,3 ,4 ]
Graves, Moira C. [2 ,3 ,4 ]
Fay, Michael [2 ,3 ,4 ,5 ]
Day, Bryan W. [6 ]
Stringer, Brett W. [7 ]
Tooney, Paul A. [1 ,2 ,3 ]
机构
[1] Univ Newcastle, Coll Hlth Med & Wellbeing, Sch Biomed Sci & Pharm, Newcastle, NSW 2308, Australia
[2] Univ Newcastle, Ctr Drug Repurposing & Med Res, Newcastle, NSW 2308, Australia
[3] Hunter Med Res Inst, New Lambton Hts, NSW 2305, Australia
[4] Univ Newcastle, Coll Hlth Med & Wellbeing, Sch Med & Publ Hlth, Newcastle, NSW 2308, Australia
[5] GenesisCare, Newcastle, NSW 2290, Australia
[6] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia
[7] Flinders Univ S Australia, Coll Med & Publ Hlth, Adelaide, SA 5042, Australia
关键词
glioblastoma; DNA damage response; treatment resistance; temozolomide; radiation; S-PHASE; REPAIR; CANCER; O-6-METHYLGUANINE; INHIBITION; EXPRESSION; APOPTOSIS; PATHWAY; RAD51; MGMT;
D O I
10.3390/cells11071215
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RT-treated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition.
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页数:15
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