TY - JOUR
T1 - SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells
AU - Yan, Yuelong
AU - Teng, Hongqi
AU - Hang, Qinglei
AU - Kondiparthi, Lavanya
AU - Lei, Guang
AU - Horbath, Amber
AU - Liu, Xiaoguang
AU - Mao, Chao
AU - Wu, Shiqi
AU - Zhuang, Li
AU - James You, M.
AU - Poyurovsky, Masha V.
AU - Ma, Li
AU - Olszewski, Kellen
AU - Gan, Boyi
N1 - Funding Information:
We thank Laura L. Russell from the Research Medical Library at The University of Texas MD Anderson Cancer Center for editing the manuscript. This research was supported by the Institutional Research Fund and Bridge Fund from MD Anderson Cancer Center; the Emerson Collective Cancer Research Fund; the Cancer Prevention & Research Institute of Texas grants RP220258 and RP230072; and R01CA181196, R01CA244144, R01CA247992, R01CA269646, and U54 CA274220 from the National Institutes of Health; and the N.G. and Helen T. Hawkins Distinguished Professorship for Cancer Research of The University of Texas MD Anderson Cancer Center (to B.G.); US National Institutes of Health grants R01CA166051 and R01CA269140; an American Cancer Society grant (award number: DBG-22-161-01-MM); and the Nylene Eckles Distinguished Professorship of The University of Texas MD Anderson Cancer Center (to L.M.). This research was also supported by the National Institutes of Health Cancer Center Support Grant (P30CA016672) to MD Anderson.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-39401-9
DO - 10.1038/s41467-023-39401-9
M3 - Article
C2 - 37339981
AN - SCOPUS:85162881272
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3673
ER -