期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 334, 期 -, 页码 35-46出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2017.08.019
关键词
Quinacrine; p38 MAPK; ERK; FOXP3/miR-183/beta-TrCP/SP1 axis; BAX upregulation
资金
- Ministry of Science and Technology, Taiwan, ROC [MOST106-2320-8110-002-MY3]
- Taiwan Protein Project [MOST 106-0210-01-15-04]
Quinacrine, which is clinically used as an antimalarial drug, has anti-cancer activity. However, mechanism underlying its cytotoxic effect remains to be completely elucidated. In the present study, we investigated the cytotoxic effect of quinacrine on human leukemia U937 cells. Quinacrine-induced apoptosis of U937 cells was accompanied with ROS generation, mitochondrial depolarization, and BAX upregulation. Quinacrine-treated U937 cells showed ROS-mediated p38 MAPK activation and ERK inactivation, which in turn upregulated FOXP3 transcription. FOXP3-mediated miR-183 expression decreased beta-TrCP mRNA stability and suppressed beta-TrCP-mediated SP1 degradation, thus increasing SP1 expression in U937 cells. Upregulated SP1 expression further increased BAX expression. BAX knock-down attenuated quinacrine-induced mitochondrial depolarization and increased the viability of quinacrine-treated cells. Together, our data indicate that quinacrine-induced apoptosis of U937 cells is mediated by mitochondrial alterations triggered by FOXP3/miR-183/beta-TrCP/SP1 axis-mediated BAX upregulation.
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