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

Abstract

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.

Beta-Transducin Repeats-Containing Proteins as an Anticancer Target

“…• reduces BTRC mRNA stability in response to hydroquinone [155] and quinacrine [156] in U937 cells promoting [155] suppressive [156] [155,156] miR-193a-3p β-TrCP1…”

“…Hydroquinone (HQ) induces the demethylation of the Forkhead box protein P3 (FOXP3) gene, resulting in FOXP3 gene expression in U937 cells [155]. As a result, FOXP3 induces the expression of miR-183, leading to a reduction in β-TrCP1 mRNA stability.…”

Identification of potential pathways and microRNA-mRNA networks associated with benzene metabolite hydroquinone-induced hematotoxicity in human leukemia K562 cells

“…Extensive research has shown that HQ may contribute to benzene-induced leukemia by oxidative stress, DNA damage, cell cycle regulation, and apoptosis [ 4 – 10 ]. HQ can inhibit erythroid differentiation in HD3 chicken erythroblast cells, K562 human leukemia cells, and U937 human leukemia cells [ 4 , 11 – 14 ]. Our previous studies suggest that benzene metabolite phenol, 1,2,4-benzenetriol, and HQ considerably inhibit hemin-induced erythroid differentiation in K562 cells [ 14 , 15 ].…”

Efeito da exposição à hidroquinona na resposta imune adaptativa induzida pela vacina contra a influenza

“…O maior tempo de exposição foi empregado com base na literatura em estudos de exposição à fumaça de cigarro para avaliação da toxicidade ao sistema imune e pulmonar, que variaram de 4 semanas ou mais de exposição (LIANG et al, 2018;SINZATO et al, 2018;VAZ et al, 2015;ZHOU et al, 2018) SNYDER, 2012;STABBERT et al, 2017). Considerando que a HQ é um dos principais produtos desta metabolização e estudos in vitro e in vivo mostram que a HQ inibe a proliferação de linfócitos, induz apoptose e causa genotoxicidade nas células da medula óssea, tem sido atribuído que a HQ seja o metabólito do BZ responsável pela toxicidade na medula (CHEN et al, 2017;LAU et al, 2009;MILLER et al, 1994;MORAN et al, 1996;RUIZ-RAMOS et al, 2017). Os dados aqui obtidos mostraram que a exposição à HQ reduziu a série eritrocítica, embora em pequena magnitude, após poucas semanas de exposição.…”