磺胺嗪用于治疗肾上腺皮质癌的新型重新利用，可能通过SLC7A11/XCT-HSA-MIR-92A-92A-3P-OIP5-AS1网络途径
Novel repurposing of sulfasalazine for the treatment of adrenocortical carcinomas, probably through the SLC7A11/xCT-hsa-miR-92a-3p-OIP5-AS1 network pathway
影响因子:2.70000
分区:医学2区 / 外科2区
发表日期:2025 Jan
作者:
Chitra Subramanian, Kelli McNamara, Seth W Croslow, Yanqi Tan, Daniel Hess, Katja Kiseljak-Vassiliades, Margaret E Wierman, Jonathan V Sweedler, Mark S Cohen
摘要
肾上腺皮质癌（ACC）的最新多基因组分析鉴定出SLC7A11/XCT是一种新型的生物标志物。食品和药物管理局批准的抗炎药，磺胺贺嗪（SAS），通过阻断SLC7A11表达来诱导铁铁作用。我们假设可以将SAS重新用于靶向ACC细胞。SLC7A11的表达及其与ACC生存的关联，使用基因表达分析互动分析（GEPIA）分析。经过验证的ACC细胞系NCI-H295R，ACC1和ACC2在2D培养中生长。体外研究包括用于计算生存力的细胞晶型 - 蛋白质印迹（WB）分析（WB）分析和其他靶蛋白质变化，逆转录酶聚合酶链的逆转录酶聚合酶链反应，用于固醇生成酶的变化，C11bodipy，用于脂质过氧化的脂质过氧化物的C11bodipy，以及对Lipid的质谱分析的质谱。非编码RNA OAP5-AS1在ACC肿瘤与正常肾上腺相比高度表达（n = 77 vs 128; p <.05）。这与SLC7A11的总体和无疾病生存率较差，危险比分别为4.3和5.2，OAP5-AS1分别为4.8和2.7。 SAS治疗72小时后，ACC细胞系的最大最大浓度值范围为412 nm（ACC1）至799 nm（ACC2），并且所有均显示出聚（ADP-核糖）聚合酶的切割，P-AKT和P-ERK的上调，以及GPX4和Slc7a11（p-akt and p-erk）的上调。球体的形成，迁移和侵袭测定法显示了使用C11bodipy的脂质过氧化，细胞内铁的增加，氧化应激的诱导以及氧化多饱和脂肪酸磷脂的显着上调（p <.05）（p <.05）（p <.05）（p <.05）均表明，质谱降低了拟南芥，使得ferfers.sass sass sass sass the sass sass sass sass tir tir the fertrem sasss tir tir ferepos。 AKT/ERK途径和脂质代谢，并在体外诱导细胞死亡，需要进行其他转化研究以确定其在ACC中的治疗潜力。
Abstract
Recent multigenomic analysis of adrenocortical carcinomas (ACCs) identified SLC7A11/xCT as a novel biomarker. The Food and Drug Administration-approved anti-inflammatory drug, sulfasalazine (SAS), induces ferroptosis by blocking SLC7A11 expression. We hypothesize that SAS could be repurposed to target ACC cells.Expression of SLC7A11 and its association with ACC survival was analyzed using Gene Expression Profiling Interactive Analysis (GEPIA). The validated ACC cell lines NCI-H295R, ACC1, and ACC2 were grown in 2D culture. In vitro studies included the CellTiter-Glo assay to calculate viability, Western blot (WB) analysis for apoptosis and other target protein changes, reverse transcriptase polymerase chain reaction for steroidogenic enzyme changes, C11BODIPY for lipid peroxidation, and mass spectrometry for changes in lipids.The Cancer Genome Atlas Program database analysis in GEPIA showed that SLC7A11 and linked long noncoding RNA OAP5-AS1 are highly expressed in ACC tumors versus normal adrenals (n = 77 vs 128; P < .05). This was associated with poor overall and disease-free survival with hazard ratios of 4.3 and 5.2 for SLC7A11 and 4.8 and 2.7 for OAP5-AS1, respectively. ACC cell line half-inhibitory maximum concentration values after 72-hour SAS treatment ranged from 412 nM (ACC1) to 799 nM (ACC2), and all showed cleavage of poly (ADP-ribose) polymerase, upregulation of p-Akt and p-ERK, and downregulation of GPX4 and SLC7A11 (P < .05) by WB analysis. Sphere formation, migration, and invasion assay showed inhibition, and lipid peroxidation using C11BODIPY, increase in intracellular iron, induction of oxidative stress, and significant upregulation of oxidized polyunsaturated fatty acid phospholipids (P < .05 each) by mass spectrometry suggests induction of ferroptosis.SAS downregulates tSLC7A11 in ACCs, targets the Akt/ERK pathway and lipid metabolism, and induces cell death in vitro, warranting additional translational studies to define its therapeutic potential in ACC.