Inhibition of DNA-dependent protein kinase catalytic subunit by small molecule inhibitor NU7026 sensitizes human leukemic K562 cells to benzene metabolite-induced apoptosis.
10.1007/s11596-013-1069-z
- Author:
Hao YOU
1
;
Meng-meng KONG
;
Li-ping WANG
;
Xiao XIAO
;
Han-lin LIAO
;
Zhuo-yue BI
;
Hong YAN
;
Hong WANG
;
Chun-hong WANG
;
Qiang MA
;
Yan-qun LIU
;
Yong-yi BI
Author Information
1. School of Public Health, Wuhan University, Wuhan, 430071, China. yh568739@yahoo.com.cn
- Publication Type:Journal Article
- MeSH:
Apoptosis;
drug effects;
physiology;
Benzene;
toxicity;
Catalysis;
Chromones;
pharmacology;
DNA Damage;
drug effects;
genetics;
DNA Repair;
drug effects;
physiology;
DNA-Activated Protein Kinase;
antagonists & inhibitors;
metabolism;
Humans;
K562 Cells;
Morpholines;
pharmacology;
Protein Subunits
- From:
Journal of Huazhong University of Science and Technology (Medical Sciences)
2013;33(1):43-50
- CountryChina
- Language:English
-
Abstract:
Benzene is an established leukotoxin and leukemogen in humans. We have previously reported that exposure of workers to benzene and to benzene metabolite hydroquinone in cultured cells induced DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to mediate the cellular response to DNA double strand break (DSB) caused by DNA-damaging metabolites. In this study, we used a new, small molecule, a selective inhibitor of DNA-PKcs, 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026), as a probe to analyze the molecular events and pathways in hydroquinone-induced DNA DSB repair and apoptosis. Inhibition of DNA-PKcs by NU7026 markedly potentiated the apoptotic and growth inhibitory effects of hydroquinone in proerythroid leukemic K562 cells in a dose-dependent manner. Treatment with NU7026 did not alter the production of reactive oxygen species and oxidative stress by hydroquinone but repressed the protein level of DNA-PKcs and blocked the induction of the kinase mRNA and protein expression by hydroquinone. Moreover, hydroquinone increased the phosphorylation of Akt to activate Akt, whereas co-treatment with NU7026 prevented the activation of Akt by hydroquinone. Lastly, hydroquinone and NU7026 exhibited synergistic effects on promoting apoptosis by increasing the protein levels of pro-apoptotic proteins Bax and caspase-3 but decreasing the protein expression of anti-apoptotic protein Bcl-2. Taken together, the findings reveal a central role of DNA-PKcs in hydroquinone-induced hematotoxicity in which it coordinates DNA DSB repair, cell cycle progression, and apoptosis to regulate the response to hydroquinone-induced DNA damage.
