Title |
Inhibition of DNA-dependent protein kinase catalytic subunit by small molecule inhibitor NU7026 sensitizes human leukemic K562 cells to benzene metabolite-induced apoptosis
|
---|---|
Published in |
Current Medical Science, February 2013
|
DOI | 10.1007/s11596-013-1069-z |
Pubmed ID | |
Authors |
Hao You, 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 |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 11 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 5 | 45% |
Student > Master | 2 | 18% |
Other | 1 | 9% |
Researcher | 1 | 9% |
Unknown | 2 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 4 | 36% |
Agricultural and Biological Sciences | 2 | 18% |
Business, Management and Accounting | 1 | 9% |
Medicine and Dentistry | 1 | 9% |
Unknown | 3 | 27% |