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首页> 外文期刊>Molecular Cancer >6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells
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6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

机译：6-甲酰基吲哚并（3,2-b）咔唑（FICZ）增强视黄酸（RA）诱导的HL-60骨髓小细胞白血病细胞的分化

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Background The aryl hydrocarbon receptor (AhR) ligand 6-Formylindolo(3,2-b)carbazole (FICZ) has received increasing attention since its identification as an endogenous AhR ligand and a photoproduct of tryptophan. FICZ and its metabolites have been detected in human fluids. We recently reported that AhR promotes retinoic acid (RA)-induced granulocytic differentiation of HL-60 myeloblastic leukemia cells by restricting the nuclear abundance of the stem cell associated transcription factor Oct4. The standard clinical management of acute promyelocytic leukemia (APL) is differentiation induction therapy using RA. But RA is not effective for other myeloid leukemias, making the mechanism of RA-induced differentiation observed in a non-APL myeloid leukemia of interest. To our knowledge, this is the first study regarding the influence of FICZ on RA-induced differentiation in any type of leukemic blasts. Methods Using flow cytometry and Western blotting assays, we determined the effects of FICZ on RA-induced differentiation of HL-60 human leukemia cells. All experiments were performed in triplicate. The groups RA and FICZ + RA were compared using the Paired-Samples T -Test. Western blot figures present the typical blots. Results We demonstrate that FICZ enhances RA-induced differentiation, assessed by the expression of the membrane differentiation marker CD11b; cell cycle arrest; and the functional differentiation marker, inducible-oxidative metabolism. FICZ causes changes in signaling events that are known to drive differentiation, and notably augments the RA-induced sustained activation of the RAF/MEK/ERK axis of the mitogen-activated protein kinase ( MAPK ) cascade. FICZ also augments expression of the known MAPK signaling regulatory molecules c-Cbl, VAV1, pY458 p85 PI3K , Src-family kinases (SFKs), and IRF-1 , a transcription factor associated with this putative signalsome that promotes RA-induced differentiation. Moreover, FICZ in combination with RA also increases expression of AhR and even more so of both Cyp1A2 and p47phox, which are known to be transcriptionally regulated by AhR. pY1021 PDGFRβ, a marker associated with retinoic acid syndrome was also increased. Conclusions Our data suggest that FICZ modulates intracellular signaling pathways and enhances RA-induced differentiation.
机译：背景芳烃受体（AhR）配体6-甲酰基吲哚（3,2-b）咔唑（FICZ）自从被鉴定为内源性AhR配体和色氨酸的光产物以来，受到越来越多的关注。 FICZ及其代谢物已在人体液体中检测到。我们最近报道，AhR通过限制干细胞相关转录因子Oct4的核丰度，促进视黄酸（RA）诱导的HL-60骨髓小细胞白血病细胞的粒细胞分化。急性早幼粒细胞白血病（APL）的标准临床管理是使用RA进行分化诱导治疗。但是RA对其他髓样白血病无效，这使得在非APL髓样白血病中观察到RA诱导分化的机制。据我们所知，这是关于FICZ对任何类型的白血病母细胞中RA诱导分化的影响的第一项研究。方法使用流式细胞仪和蛋白质印迹法，我们测定了FICZ对RA诱导的HL-60人白血病细胞分化的影响。所有实验均重复三次。使用配对样本T检验比较RA组和FICZ + RA。蛋白质印迹图代表典型的印迹。结果我们证明FICZ增强了RA诱导的分化，通过膜分化标志物CD11b的表达来评估;细胞周期停滞;和功能分化标志物，诱导氧化代谢。 FICZ引起已知驱动分化的信号事件发生变化，并显着增强了RA诱导的丝裂原活化蛋白激酶（MAPK）级联的RAF / MEK / ERK轴的持续激活。 FICZ还增强了已知的MAPK信号调节分子c-Cbl，VAV1，pY458 p85 PI3K，Src家族激酶（SFK）和IRF-1的表达，IRF-1是与这种可能的信号体相关的转录因子，可促进RA诱导的分化。此外，FICZ与RA的结合还可以增加AhR的表达，甚至还可以增加Cyp1A2和p47phox的表达，已知Cyp1A2和p47phox受AhR转录调控。与视黄酸综合征相关的标志物pY1021PDGFRβ也增加了。结论我们的数据表明FICZ调节细胞内信号通路并增强RA诱导的分化。

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