BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-02-15 DOI:10.1016/j.molmet.2025.102113

Se Seul Im , Jihyeon Seo , Ji Eun You , Hye Won Bang , YongHwan Kim , Jiyeon Kweon , Yongsub Kim , Dong-Myung Shin , Jaekyoung Son

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引用次数: 0

Abstract

Objectives

Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.

Methods

The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.

Results

BIX significantly inhibited the growth of PDAC cells, both in vitro and in vivo, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP⁺/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-l-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.

Conclusions

Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.

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BIX01294通过抑制谷氨酰胺酶介导的谷胱甘肽动力学来抑制PDAC的生长。

目的：谷氨酰胺酶（GLS）表达升高与乳腺癌、肺癌和胰腺癌等多种癌症患者的侵袭性疾病和较差预后相关。G9a组蛋白甲基转移酶抑制剂可能具有抗癌活性。本研究评估了G9a组蛋白甲基转移酶抑制剂BIX01294 （BIX）是否能抑制胰导管腺癌（PDAC）细胞中的谷氨酰胺酶（GLS）。方法：采用靶向液相色谱-串联质谱（LC-MS/MS）代谢组学分析方法评价BIX对PDAC细胞线粒体代谢的影响。为了评估BIX对谷胱甘肽动力学的影响，采用基于fresh示踪剂的谷胱甘肽测定法监测谷胱甘肽水平的实时变化。结果：BIX在体外和体内均能显著抑制PDAC细胞的生长，并能强烈诱导凋亡细胞死亡。BIX显著提高细胞内NADP+/NADPH比值，降低还原性氧化谷胱甘肽（GSH:GSSG）比值。此外，BIX降低GSH水平，增加ROS水平。补充n -乙酰- l-半胱氨酸（NAC）可显著拯救bix诱导的PDAC细胞凋亡。此外，BIX通过抑制jumonji结构域组蛋白去甲基化酶而非G9a组蛋白甲基转移酶来抑制GLS的转录。一种jumonji结构域组蛋白去甲基化酶KDM6B通过结合GLS基因启动子在表观遗传学上调控GLS表达。结论：总的来说，这些发现表明BIX可能通过抑制gls介导的细胞氧化还原平衡而成为PDAC患者的有效治疗剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.