DNA-PKcs Inhibition Sensitizes Cancer Cells to Carbon-Ion Irradiation via Telomere Capping Disruption

doi:10.1371/journal.pone.0072641

	DNA-PKcs Inhibition Sensitizes Cancer Cells to Carbon-Ion Irradiation via Telomere Capping Disruption
	Zhou, Xin1,2,3 ; Zhang, Xin1,2,3 ; Xie, Yi1,2,3 ; Tanaka, Kaoru 4; Wang, Bing 4; Zhang, Hong1,2,3
刊名	PLOS ONE
	2013-08-27
卷号	8
ISSN号	1932-6203
DOI	10.1371/journal.pone.0072641
文献子类	Article
英文摘要	Heavy-ion irradiation induces a higher frequency of DNA double strand breaks (DSBs) which must be properly repaired. Critical shortening of telomeres can trigger DNA damage responses such as DSBs. Telomeres are very sensitive to oxidative stress such as ionizing radiation. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is the central component in the non-homologous end joining (NHEJ) repair complex and participates in telomere maintenance. Therefore, it is expected to enhance the cell killing effect of heavy-ion irradiation via DNA-PKcs inhibition. To test this hypothesis, cellular radiosensitivity was measured by the clonal genetic assay. DNA damage repair was relatively quantified by long PCR. Apoptosis was quantified by flow-cytometric analysis of annexin V/PI double staining, and senescence was analyzed by galactosidase activity. Telomere length was semi-quantified by real-time PCR. P53 and p21 expression was determined by western blotting. Our data demonstrated that MCF-7 and HeLa cells with DNA-PKcs inhibition were more susceptible to carbon-ion irradiation than Those without DNA-PKcs inhibition. Even though NHEJ was inhibited by the DNA-PKcs specific inhibitor, NU7026, most DNA damage induced by carbon-ion irradiation was repaired within 24 hours after irradiation in both cell lines. However, potential lethal damage repair (PLDR) could not restore cellular inactivation in DNA-PKcs inhibited cells. MCF-7 cells showed extensive senescence and accelerated telomere length reduction, while HeLa cells underwent significant apoptosis after irradiation with NU7026 incubation. In addition, both cell lines with shorter telomere were more susceptible to carbon-ion radiation. Our current data suggested that DNA-PKcs inhibition could enhance cellular sensitivity to carbon-ion radiation via disturbing its functional role in telomere end protection. The combination of DNA-PKcs inhibition and carbon-ion irradiation may be an efficient method of heavy-ion therapy.
资助项目	National Institute of Radiological Sciences[11J364]
WOS关键词	DOUBLE-STRAND BREAKS ; IONIZING-RADIATION ; HOMOLOGOUS RECOMBINATION ; REPAIR ; MAINTENANCE ; INSTABILITY ; DYSFUNCTION ; STRESS ; NBS1
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000323815200051
内容类型	期刊论文
源URL	[http://119.78.100.186/handle/113462/48477]
专题	中国科学院近代物理研究所
通讯作者	Zhang, Hong
作者单位	1.Chinese Acad Sci, Inst Modern Phys, Dept Heavy Ion Radiat Med, Lanzhou, Peoples R China 2.Chinese Acad Sci, Key Lab Heavy Ion Radiat Biol & Med, Lanzhou, Peoples R China 3.Key Lab Heavy Ion Radiat Med Gansu Prov, Lanzhou, Peoples R China 4.Natl Inst Radiol Sci, Res Ctr Radiat Protect, Radiat Risk Reduct Res Program, Inage Ku, Chiba 260, Japan
推荐引用方式 GB/T 7714	Zhou, Xin,Zhang, Xin,Xie, Yi,et al. DNA-PKcs Inhibition Sensitizes Cancer Cells to Carbon-Ion Irradiation via Telomere Capping Disruption[J]. PLOS ONE,2013,8.
APA	Zhou, Xin,Zhang, Xin,Xie, Yi,Tanaka, Kaoru,Wang, Bing,&Zhang, Hong.(2013).DNA-PKcs Inhibition Sensitizes Cancer Cells to Carbon-Ion Irradiation via Telomere Capping Disruption.PLOS ONE,8.
MLA	Zhou, Xin,et al."DNA-PKcs Inhibition Sensitizes Cancer Cells to Carbon-Ion Irradiation via Telomere Capping Disruption".PLOS ONE 8(2013).