文章：

KATP通道抑制剂通过上调弥漫性内生性桥脑胶质瘤中H3K27ac抑制细胞增殖：一项功能性表达研究

KATP Channel Inhibitors Reduce Cell Proliferation Through Upregulation of H3K27ac in Diffuse Intrinsic Pontine Glioma: A Functional Expression Investigation

原文发布日期：22 January 2025

DOI: 10.3390/cancers17030358

类型: Article

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英文摘要：

Background: Diffuse intrinsic pontine glioma [DIPG] is a fatal pediatric disease characterized by a post-translational modification, a replacement of lysine by methionine in position 27 of the N-terminal [H3K27M] tail of histone 3 isoform-1 [H3.1] or histone 3 isoform-3 [H3.3], respectively, expressed in the DIPG-36 and DIPG-50 cells. We investigated the role of cation channels in DIPG cells for the first time and the effects of ATP-sensitive K+[KATP] and TRPV1 channel modulators. Methods: Experiments were performed using “in vitro” cytotoxic assays combined with the patch clamp technique, RT-PCR, Western blot, and flow cytometry assays. Results: The most effective anti-proliferative drugs were repaglinide and glibenclamide after short and long-term incubation [6–96 h]. These drugs reduced macroscopic currents of the DIPG cells recorded in whole-cell patch clamp. Repaglinide concentration dependently enhanced the target protein H3K27ac in Western blotting after 48 h of incubation. This drug reduced cell diameter and enhanced cleaved caspase-3 in DIPG cells; total AKT/mTOR levels and phospho-mTOR were downregulated in DIPG-36. Conclusions: KATP and TRPV1 channels are functionally expressed, and sulphonylureas are effective antiproliferative upregulating H3K27ac with apoptosis in DIPG cells and the sub-micromolar concentrations in DIPG-50.

摘要翻译： 

背景：弥漫内生型脑桥胶质瘤（DIPG）是一种致命的儿童疾病，其特征表现为翻译后修饰，即在DIPG-36和DIPG-50细胞中表达的组蛋白3亚型-1（H3.1）或组蛋白3亚型-3（H3.3）N端尾部第27位赖氨酸被甲硫氨酸取代（H3K27M）。本研究首次探讨了阳离子通道在DIPG细胞中的作用，以及ATP敏感性钾离子通道（KATP）和TRPV1通道调节剂的影响。方法：采用体外细胞毒性实验结合膜片钳技术、RT-PCR、Western blot和流式细胞术进行实验。结果：短期和长期孵育（6-96小时）后，最有效的抗增殖药物为瑞格列奈和格列本脲。这些药物降低了全细胞膜片钳记录的DIPG细胞宏观电流。孵育48小时后，瑞格列奈浓度依赖性地增强了Western blot中靶蛋白H3K27ac的表达。该药物减小了DIPG细胞直径并增强了cleaved caspase-3表达；在DIPG-36细胞中，总AKT/mTOR水平和磷酸化mTOR表达下调。结论：KATP和TRPV1通道在DIPG细胞中具有功能性表达，磺脲类药物在亚微摩尔浓度下能通过上调H3K27ac诱导细胞凋亡，对DIPG-50细胞具有显著抗增殖效果。

原文链接：

KATP Channel Inhibitors Reduce Cell Proliferation Through Upregulation of H3K27ac in Diffuse Intrinsic Pontine Glioma: A Functional Expression Investigation