Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells

详细信息    查看全文

• 作者：Ying-Jung Chen ; Wen-Hsin Liu ; Long-Sen Chang
• 关键词：Hydroquinone ; Leukemia ; FOXP3 ; Malignant progression ; ADAM17/Lyn/Akt/p21 axis
• 刊名：Archives of Toxicology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：91
• 期：2
• 页码：983-997
• 全文大小：
• 刊物主题：Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine, general;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0738
• 卷排序：91

文摘

Hydroquinone (1,4-benzenediol; HQ), a major marrow metabolite of the leukemogen benzene, has been proven to evoke benzene-related hematological disorders and myelotoxicity in vitro and in vivo. The goal of the present study was to explore the role of FOXP3 in HQ-induced malignant progression of U937 human leukemia cells. U937 cells were treated with 5 μM HQ for 24 h, and the cells were re-suspended in serum-containing medium without HQ for 2 days. The same procedure was repeated three times, and the resulting U937/HQ cells were maintained in cultured medium containing 5 μM HQ. Proliferation and colony formation of U937/HQ cells were notably higher than those of U937 cells. Ten-eleven translocation methylcytosine dioxygenase-mediated demethylation of the Treg-specific demethylated region in FOXP3 gene resulted in higher FOXP3 expression in U937/HQ cells than in U937 cells. FOXP3-induced miR-183 expression reduced β-TrCP mRNA stability and suppressed β-TrCP-mediated Sp1 degradation, leading to up-regulation of Sp1 expression in U937/HQ cells. Sp1 up-regulation further increased ADAM17 and Lyn expression, and ADAM17 up-regulation stimulated Lyn activation in U937/HQ cells. Moreover, U937/HQ cells showed higher Lyn-mediated Akt activation and cytoplasmic p21 expression than U937 cells did. Abolishment of Akt activation decreased cytoplasmic p21 expression in U937/HQ cells. Suppression of FOXP3, ADAM17, and Lyn expression, as well as Akt inactivation, repressed proliferation and clonogenicity of U937/HQ cells. Together with the finding that cytoplasmic p21 shows anti-apoptotic and oncogenic activities in cancer cells, the present data suggest a role of FOXP3/ADAM17/Lyn/Akt/p21 signaling axis in HQ-induced hematological disorders.