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KATP通道抑制剂通过上调弥漫性脑桥内生胶质瘤中H3K27ac来减少细胞增殖：一项功能表达研究

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

作者信息

Antonacci Marina, Maqoud Fatima, Di Turi Annamaria, Miciaccia Morena, Perrone Maria Grazia, Scilimati Antonio, Tricarico Domenico

机构信息

Department of Pharmacy-Pharmaceutical Sciences, University of Bari "Aldo Moro", 70125 Bari, Italy.

Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology Saverio de Bellis, I.R.C.C.S. Research Hospital, 70013 Castellana Grotte, Italy.

出版信息

Cancers (Basel). 2025 Jan 22;17(3):358. doi: 10.3390/cancers17030358.

DOI:10.3390/cancers17030358
PMID:39941728
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11816144/
Abstract

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

背景

弥漫性脑桥内在型胶质瘤（DIPG）是一种致命的儿科疾病，其特征在于翻译后修饰，即分别在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）的N端[H3K27M]尾部第27位赖氨酸被甲硫氨酸取代。我们首次研究了阳离子通道在DIPG细胞中的作用以及ATP敏感性钾通道（KATP）和瞬时受体电位香草酸亚型1（TRPV1）通道调节剂的作用。

方法

采用“体外”细胞毒性试验结合膜片钳技术、逆转录 - 聚合酶链反应（RT - PCR）、蛋白质免疫印迹法（Western blot）和流式细胞术检测进行实验。

结果

短期和长期孵育（6 - 96小时）后，最有效的抗增殖药物是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细胞的宏观电流。孵育48小时后，瑞格列奈浓度依赖性地增强了蛋白质免疫印迹中的靶蛋白H3K27ac。该药物减小了DIPG细胞的直径并增强了DIPG细胞中裂解的半胱天冬酶 - 3；DIPG - 36中的总AKT/mTOR水平和磷酸化mTOR下调。

结论

KATP和TRPV1通道有功能表达，磺酰脲类药物在DIPG细胞中是有效的抗增殖药物，可上调H3K27ac并诱导凋亡，在DIPG - 50中的浓度为亚微摩尔级。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/14df91a8a1f7/cancers-17-00358-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/8b9eaad59da0/cancers-17-00358-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/a2b532229195/cancers-17-00358-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/13eb96f9439b/cancers-17-00358-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/5e61265d4738/cancers-17-00358-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/79770a52f94d/cancers-17-00358-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/14df91a8a1f7/cancers-17-00358-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/8b9eaad59da0/cancers-17-00358-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/0b39bad75382/cancers-17-00358-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/04d1ae050c30/cancers-17-00358-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/b2906fa544d3/cancers-17-00358-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/d51a73dea396/cancers-17-00358-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/d60de04c676f/cancers-17-00358-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/a2b532229195/cancers-17-00358-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/390e42fe3b02/cancers-17-00358-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/13eb96f9439b/cancers-17-00358-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/5e61265d4738/cancers-17-00358-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/79770a52f94d/cancers-17-00358-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca06/11816144/14df91a8a1f7/cancers-17-00358-g012.jpg

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