Hydroquinone (HQ), a major metabolic product of benzene, causes acute myeloid leukemia (AML) elicited by benzene exposure. Past studies found that continuous exposure of human AML U937 cells to HQ selectively produces malignant U937/HQ cells in which FOXP3 upregulation modulates malignant progression. Other studies revealed that AMPK promotes TET2 activity on DNA demethylation and that TET2 activity is crucial for upregulating FOXP3 expression. This study was conducted to elucidate whether compound C, an AMPK inhibitor, blocked the AMPK–TET2–FOXP3 axis in AML and in HQ-selected malignant cells. We found higher levels of AMPKα, TET2, and FOXP3 expression in U937/HQ cells compared to U937 cells. Treatment of parental Original Article and HQ-selected malignant U937 cells with compound C induced ROS-mediated p38 MAPK activation, leading to a suppression of AMPKα, TET2, and FOXP3 expression. Moreover, compound C induced apoptosis and mTOR-independent autophagy. The suppression of the autophagic flux inhibited the apoptosis of compound C-treated U937 and U937/HQ cells, whereas co-treatment with rapamycin, a mTOR inhibitor, sensitized the two cell lines to compound C cytotoxicity. Overexpression of AMPKα1 or pretreatment with autophagic inhibitors abrogated compound C-induced autophagy and suppression of TET2 and FOXP3 expression. Restoration of AMPKα1 or FOXP3 expression increased cell survival after treatment with compound C. In conclusion, our results show that compound C suppresses AMPK/TET2 axis-mediated FOXP3 expression and induces autophagy-dependent apoptosis in parental and HQ-selected malignant U937 cells, suggesting that the AMPK/TET2/FOXP3 axis is a promising target for improving AML therapy and attenuating benzene exposure-induced AML progression.

中文翻译：

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化合物 C 通过 ROS/p38 MAPK/AMPK/TET2/FOXP3 轴在亲本和对苯二酚选择的恶性白血病细胞中诱导自噬和凋亡。

苯的主要代谢产物对苯二酚 (HQ) 会导致由苯暴露引起的急性髓系白血病 (AML) 。过去的研究发现，人类 AML U937 细胞持续暴露于 HQ 会选择性地产生恶性 U937/HQ 细胞，其中 FOXP3 上调调节恶性进展。其他研究表明，AMPK 促进 TET2 对 DNA 去甲基化的活性，并且 TET2 活性对于上调 FOXP3 表达至关重要。本研究旨在阐明化合物 C（一种 AMPK 抑制剂）是否阻断了 AML 和 HQ 选择的恶性细胞中的 AMPK-TET2-FOXP3 轴。我们发现与 U937 细胞相比，U937/HQ 细胞中 AMPKα、TET2 和 FOXP3 表达水平更高。用化合物 C 处理亲本 Original Article 和 HQ 选择的恶性 U937 细胞会诱导 ROS 介导的 p38 MAPK 活化，从而抑制 AMPKα、TET2 和 FOXP3 的表达。此外，化合物 C 诱导细胞凋亡和不依赖于 mTOR 的自噬。自噬流的抑制抑制了化合物 C 处理的 U937 和 U937/HQ 细胞的凋亡，而与雷帕霉素（一种 mTOR 抑制剂）的共同处理使两种细胞系对化合物 C 的细胞毒性敏感。AMPKα1 的过表达或用自噬抑制剂预处理消除了化合物 C 诱导的自噬和 TET2 和 FOXP3 表达的抑制。AMPKα1 或 FOXP3 表达的恢复增加了用化合物 C 处理后的细胞存活率。 总之，我们的结果表明，化合物 C 抑制了 AMPK/TET2 轴介导的 FOXP3 表达并诱导了亲本和 HQ 选择的恶性 U937 细胞的自噬依赖性细胞凋亡，表明AMPK/TET2/FOXP3 轴是改善 AML 治疗和减轻苯暴露诱导的 AML 进展的有希望的目标。