Upregulation of SLC7A11/xCT creates a vulnerability to selenocystine-induced cytotoxicity.

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 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 upregulate SLC7A11 expression.

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