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SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

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.

SUBMITTER: Yan Y

PROVIDER: S-EPMC10281978 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

Yan Yuelong Y Teng Hongqi H Hang Qinglei Q Kondiparthi Lavanya L Lei Guang G Horbath Amber A Liu Xiaoguang X Mao Chao C Wu Shiqi S Zhuang Li L James You M M Poyurovsky Masha V MV Ma Li L Olszewski Kellen K Gan Boyi B

Nature communications 20230621 1

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 ...[more]

PMID: 37339981

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Project description:ObjectiveRedox adaptation plays a critical role in cancer cells' drug tolerance and sensitivity. The antioxidative response is induced by nuclear factor erythroid 2-related factor 2 (Nrf2), which triggers the transcriptional activation of genes related to chemosensitivity, glutathione synthesis, and cell protection. Although Nestin1 is known to regulate cellular redox homeostasis by regulating Nrf2 in lung cancer cells, its regulatory effect on the antioxidative state of bladder cancer (BC) cells remains unclear.MethodsThe oxidative stress levels in two cisplatin-treated BC cell lines (T24 and J82) were examined using 2',7'-dichlorofluorescin diacetate staining and real-time quantitative reverse transcription-PCR (RT-qPCR) assays. The cell viability, growth, and apoptosis were determined using CCK-8, colony formation, and flow cytometric assays, respectively. The mRNA and protein levels of Nestin1, Nrf2, and several antioxidant enzymes were quantified using RT-qPCR and western blot assays. A mouse xenograft model was used to determine the effect of Nestin1 on the T24 tumor growth in vivo.ResultsCisplatin treatment induced reactive oxygen species (ROS) generation and antioxidative damage in the T24 and J82 cells, reducing their viability and growth and triggering their apoptosis. Moreover, the Nestin1 and Nrf2 protein levels were enhanced in both treated cell lines. Loss- and gain-of-function assays indicated that Nestin1 expression was positively correlated with the Nrf2 protein expression in the BC cells. Nestin1 overexpression reduced the ROS generation, alleviated the redox disorder, promoted cell viability, and reduced apoptosis, but its silencing had the opposite effects. Importantly, Nestin1 overexpression enhanced the chemoresistance of BC cells to cisplatin in vivo, but its knockdown improved the chemosensitivity of the cells and increased their apoptosis.ConclusionThese results provide a theoretical basis for further targeting the transcription factors, including Nestin1 and Nrf2, in the treatment of BC with cisplatin.

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SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

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SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

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