The SLC7A11/xCT cystine and glutamate antiporter has emerged as an attractive target for cancer therapy due to its selective overexpression in multiple cancers and its role in preventing ferroptosis. Utilizing pharmacological and genetic approaches in hepatocellular carcinoma cell lines, we demonstrate that overexpression of SLC7A11 engenders hypersensitivity towards l-selenocystine, a naturally occurring diselenide that bears close structural similarity to l-cystine. We find that the abundance of SLC7A11 positively correlates with sensitivity to l-selenocystine, but surprisingly, not to Erastin, an inhibitor of SLC7A11 activity. Our data indicate that SLC7A11 acts as a transport channel for l-selenocystine, which preferentially incites acute oxidative stress and damage eventuating to cell death in cells that highly express SLC7A11. Hence, our findings raise the prospect of l-selenocystine administration as a novel strategy for targeting cancers that up-regulate SLC7A11 expression.

中文翻译：

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SLC7A11/xCT 的上调易受硒代胱氨酸诱导的细胞毒性的影响

SLC7A11/xCT 胱氨酸和谷氨酸逆向转运蛋白已成为癌症治疗的一个有吸引力的靶标，因为它在多种癌症中选择性过度表达及其在预防铁死亡中的作用。利用肝细胞癌细胞系中的药理学和遗传学方法，我们证明 SLC7A11 的过度表达会引起对 L-硒代胱氨酸的超敏反应，L-硒代胱氨酸是一种天然存在的二硒化物，与 L-胱氨酸具有密切的结构相似性。我们发现 SLC7A11 的丰度与 L-硒代胱氨酸的敏感性呈正相关，但令人惊讶的是，与 SLC7A11 活性抑制剂 Erastin 的敏感性无关。我们的数据表明，SLC7A11 充当 L-硒代胱氨酸的转运通道，其优先激发高度表达 SLC7A11 的细胞的急性氧化应激和损伤，最终导致细胞死亡。因此，我们的研究结果提出了将 L-硒代胱氨酸给药作为针对上调 SLC7A11 表达的癌症的新策略的前景。