最近对肾上腺皮质癌 (ACC) 的多基因组分析将 SLC7A11/xCT 确定为一种新型生物标志物。美国食品和药物管理局批准的抗炎药柳氮磺胺吡啶 (SAS) 通过阻断 SLC7A11 表达来诱导铁死亡。我们假设 SAS 可以重新用于靶向 ACC 细胞。使用基因表达谱交互分析 (GEPIA) 分析了 SLC7A11 的表达及其与 ACC 存活的关联。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活力的 CellTiter-Glo 测定、用于细胞凋亡和其他目标蛋白变化的蛋白质印迹 (WB) 分析、用于类固醇生成酶变化的逆转录酶聚合酶链反应、用于脂质过氧化的 C11BODIPY 以及用于脂质变化的质谱分析。 GEPIA 的癌症基因组图谱计划数据库分析表明，与正常肾上腺相比，SLC7A11 和连锁长非编码 RNA OAP5-AS1 在 ACC 肿瘤中高度表达（n = 77 vs 128；P < .05）。这与较差的总体生存率和无病生存率相关，SLC7A11 的风险比分别为 4.3 和 5.2，OAP5-AS1 的风险比分别为 4.8 和 2.7。 72 小时 SAS 处理后 ACC 细胞系半抑制最大浓度值范围为 412 nM (ACC1) 至 799 nM (ACC2)，并且均显示聚 (ADP-核糖) 聚合酶的裂解、p-Akt 和 p-通过 WB 分析，ERK 以及 GPX4 和 SLC7A11 下调 (P < .05)。球体形成、迁移和侵袭测定显示使用 C11BODIPY 抑制脂质过氧化、细胞内铁增加、氧化应激诱导，以及质谱分析氧化多不饱和脂肪酸磷脂的显着上调（每个 P < .05）表明诱导铁死亡.SAS 下调 ACC 中的 tSLC7A11，靶向 Akt/ERK 通路和脂质代谢，并诱导体外细胞死亡，需要进行额外的转化研究来确定其在 ACC 中的治疗潜力。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.