DNA-PKcs Inhibition Sensitizes Human Chondrosarcoma Cells to Carbon Ion Irradiation via Cell Cycle Arrest and Telomere Capping Disruption

被引:0
|
作者
Lohberger, Birgit [1 ]
Barna, Sandra [2 ,3 ]
Glaenzer, Dietmar [1 ]
Eck, Nicole [1 ]
Leithner, Andreas [1 ]
Georg, Dietmar [2 ,3 ]
机构
[1] Med Univ Graz, Dept Orthoped & Trauma, Auenbruggerpl 5-7, A-8036 Graz, Austria
[2] Med Univ Vienna, Dept Radiat Oncol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria
[3] MedAustron Ion Therapy Ctr, Viktor Kaplan Str 2, A-2700 Wiener Neustadt, Austria
关键词
carbon ion irradiation; chondrosarcoma; AZD7648; DNA-PKcs inhibitor; telomere length; C-MYC; REPAIR; RADIOTHERAPY; ACTIVATION; KINASE; DAMAGE; ATM;
D O I
10.3390/ijms25116179
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G2/M arrest. The expression of the G2/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection.
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页数:16
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