Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Antioxidants Pub Date : 2024-10-03 DOI:10.3390/antiox13101201
Fatemeh Jamali, Katherine Lan, Paul Daniel, Kevin Petrecca, Siham Sabri, Bassam Abdulkarim
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Abstract

Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene TP53, wild-type (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with a known TP53 status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT (Ser-473) phosphorylation, and increased p53, p21, and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. Additionally, p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to Auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to Auranofin in GSCs. The combination of Auranofin and L-BSO synergistically increased ROS, decreased IC50s, and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased the expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combining Auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose Auranofin and PPL in GBM.

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与 p53 无关的硫氧还蛋白和谷胱甘肽系统在胶质母细胞瘤干细胞中的协同双重靶向作用
胶质母细胞瘤(GBM)是一种无法治愈的原发性脑癌,其特点是活性氧(ROS)生成增加。对氧化还原反应敏感的肿瘤抑制基因TP53(70%的患者为野生型)调节氧化还原平衡。胶质母细胞瘤干细胞(GSCs)会增加硫氧还蛋白(Trx)和谷胱甘肽(GSH)抗氧化系统,作为生存的氧化还原适应机制,将ROS维持在细胞毒性阈值以下。美国 FDA 批准的抗类风湿药物 Auranofin 可抑制硫氧还蛋白还原酶 1(TrxR1)。L-丁硫亚胺(L-BSO)和天然产物哌隆胺(PPL)抑制 GSH 系统。我们评估了奥拉诺芬单独使用以及与 L-BSO 或 PPL 联用对已知 TP53 状态的 GBM 细胞系和 GSC 的细胞毒性作用。癌症基因组图谱/GBM分析显示,GBM中wtp53和TrxR1的表达呈显著正相关。欧拉诺芬在微摩尔范围内诱导 GSCs 中的 ROS 依赖性细胞毒性。在wtp53-GSCs中,奥拉诺芬降低了TrxR1的表达、AKT(Ser-473)的磷酸化,并增加了p53、p21和PARP-1的凋亡裂解,而在突变体-p53 GSC系中,突变体-p53的表达也有所降低。此外,在 wtp53-GSC 株系中敲除 p53 会降低 TrxR1 的表达,并显著增加对 Auranofin 的敏感性,这表明 wtp53 在 GSCs 对 Auranofin 的反应中起着负氧化还原敏感机制的作用。欧拉诺芬和 L-BSO 的联合作用协同增加了 ROS,降低了 IC50,并诱导了 GBM 细胞系和 GSCs 的长期细胞毒性,而与 p53 无关。耐人寻味的是,Auranofin 增加了谷胱甘肽 S 转移酶 pi-1 (GSTP-1)的表达,而 GSTP-1 是 PPL 的靶标。Auranofin 与 PPL 协同作用可将 GSCs 中的 IC50 降至纳摩尔范围,这支持了将 Auranofin 和 PPL 重新用于 GBM 的潜力。
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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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