SLC7A11 Expression Level Dictates Differential Responses to Oxidative Stress in Cancer Cells

Authors

Yuelong Yan
Hongqi Teng
Qinglei Hang
Lavanya Kondiparthi
Guang Lei
Amber Horbath
Xiaoguang Liu
Chao Mao
Shiqi Wu
Li Zhuang
M James You
Masha V Poyurovsky
Li Ma
Kellen Olszewski
Boyi Gan

Publication Date

6-21-2023

Journal

Nature Communications

Abstract

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells’ sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.

Keywords

Cystine, Cell Line, Tumor, Hydrogen Peroxide, Oxidative Stress, Disulfides, Amino Acid Transport System y+, Neoplasms, Cell death, Cancer metabolism

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Supplementary Materials

PMID: 37339981