Tonelotto Valentina, Costa-Garcia Marcel, O'Reilly Eve, Smith Kaelin Francis, Slater Kayleigh, Dillon Eugene T, Pendino Marzia, Higgins Catherine, Sist Paola, Bosch Rosa, Passamonti Sabina, Piulats Josep M, Villanueva Alberto, Tramer Federica, Vanella Luca, Carey Michelle, Kennedy Breandán N
UCD Conway Institute, University College Dublin, D04 V1W8, Dublin, Ireland.
UCD School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8, Dublin, Ireland.
Cell Death Discov. 2024 Feb 10;10(1):70. doi: 10.1038/s41420-023-01773-8.
Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.
葡萄膜黑色素瘤（UM）是一种眼部癌症，易于发生致命的肝转移。当发生转移性UM（MUM）时，只有8%的患者能存活超过两年。迫切需要有效的MUM治疗方法。1,4 - 二羟基奎尼替尼是一种半胱氨酰白三烯受体1（CysLT）拮抗剂，在体外、离体和体内均可改变UM的癌症特征。在此，我们研究了1,4 - 二羟基奎尼替尼的作用机制及其在MUM中的转化潜力。对OMM2.5细胞进行蛋白质组分析，确定了1,4 - 二羟基奎尼替尼处理后差异表达的蛋白质。通过免疫印迹法评估谷胱甘肽过氧化物酶4（GPX4）、谷氨酸 - 半胱氨酸连接酶修饰亚基（GCLM）、血红素加氧酶1（HO - 1）和4 - 羟基壬烯醛（4 - HNE）的表达。通过生化方法测定胆红素、谷胱甘肽和脂质氢过氧化物。使用公共数据库分析特定铁死亡特征的表达与UM患者生存之间的关联。我们的数据显示，1,4 - 二羟基奎尼替尼可调节OMM2.5细胞中铁死亡标志物的表达。生化分析证实，GPX4、胆红素、GCLM、谷胱甘肽和脂质氢过氧化物发生了显著变化。在原位患者来源异种移植（OPDX）的MUM肿瘤外植体中，HO - 1和4 - HNE水平显著升高。在3号染色体单体型的UM患者中，抑制铁死亡的基因表达显著增加。我们确定了IFerr，这是一种与UM患者生存相关的新型铁死亡特征。总之，我们证明在MUM细胞和组织中，1,4 - 二羟基奎尼替尼可调节诱导铁死亡的关键标志物，铁死亡是一种由磷脂的铁依赖性过氧化驱动的相对新型的细胞死亡。此外，我们表明抑制铁死亡的特定基因的高表达与UM预后较差相关，因此，IFerr特征是预测哪些患者会发生MUM的潜在指标。总而言之，铁死亡有潜力作为MUM的临床生物标志物和治疗靶点。
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