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Review
. 2021 Aug;12(8):599-620.
doi: 10.1007/s13238-020-00789-5. Epub 2020 Oct 1.

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

Pranavi Koppula  1   2 , Li Zhuang  1 , Boyi Gan  3   4
Affiliations
Review

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

Pranavi Koppula et al. Protein Cell. 2021 Aug.

Abstract

The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.

Keywords: SLC7A11; cancer therapy; cysteine; cystine; ferroptosis; nutrient dependency; xCT.

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Figures

Figure 1
Figure 1
Structure and function of SLC7A11. System xc− functions as a cystine/glutamate antiporter that imports one molecule of cystine in exchange for one molecule of intracellular glutamate. System xc− is a heterodimer consisting of the light chain subunit SLC7A11 and the heavy chain subunit SLC3A2. SLC7A11 mediates the antiporter activity of system xc−, whereas SLC3A2 anchors SLC7A11 to the plasma membrane and maintains SLC7A11 protein stability. Extracellular cystine is imported into the cell through SLC7A11, and then is converted to cysteine through a NADPH-consuming reduction reaction. Subsequently, cysteine is utilized to synthesize GSH through a two-step process. Cysteine forms γ-glutamylcysteine in conjugation with glutamate in the first step catalyzed by γ-GCS. The second step involves GS-mediated enzymatic addition of a glycine molecule to produce GSH. Ferroptosis is induced by excessive accumulation of lipid hydroperoxides in cellular membrane. GPX4 uses GSH to reduce lipid hydroperoxides to lipid alcohols, thereby suppressing ferroptosis, through which GSH is oxidized to GSSG; GSSG is then converted back to GSH via GR-mediated reduction reaction, which consumes NADPH. γ-GCS: γ-glutamylcysteine synthetase, GS: glutathione synthetase, GPX4: glutathione peroxidase 4, GR: glutathione reductase, GSH: reduced glutathione, GSSG: oxidized glutathione, LOOH: lipid hydroperoxide, LOH: lipid alcohol
Figure 2
Figure 2
SLC7A11 regulation by transcriptional, epigenetic, and post-translational mechanisms. SLC7A11 expression and function can be regulated at multiple levels under basal and stress conditions. Transcriptional activation: ATF4 activates SLC7A11 transcription in response to amino acid deprivation through the GCN2-eIF2α signaling axis. The KEAP1-NRF2 signaling axis regulates oxidative stress-induced SLC7A11 transcription. In response to oxidative stress, KEAP1-mediated NRF2 proteasomal degradation is suppressed, allowing stabilized NRF2 protein to translocate into the nucleus and activate the transcription of SLC7A11 and other genes involved in antioxidant response. SWI/SNF chromatin remodeling complexes facilitate NRF2-mediated transcriptional activation of SLC7A11. H3K9 demethylase KDM3B decreases H3K9 methylation on the SLC7A11 promoter and promotes SLC7A11 transcription. Transcriptional repression: Under basal conditions, p53 and ATF3 repress SLC7A11 transcription. BAP1 deubiquitinates H2Aub on the SLC7A11 promoter and subsequently represses SLC7A11, whereas H2A ubiquitination by PRC1 on the SLC7A11 promoter also represses SLC7A11. p53-mediated nuclear translocation of USP7 results in decreased H2Bub occupancy on the SLC7A11 promoter via deubiquitination, resulting in transcriptional repression. Post-translational regulation: OTUB1 and CD44 form a trimeric complex with SLC7A11 to deubiquitinate SLC7A11 and inhibit SLC7A11 degradation in proteasome, thereby stabilizing SLC7A11 protein, whereas mTORC1 promotes SLC7A11 protein stability by inhibiting its lysosomal degradation. High cell density inhibits mTORC1 and promotes SLC7A11 degradation in lysosomes. Both mTORC2 and AKT inhibit SLC7A11 transporter activity by phosphorylating SLC7A11 at serine 26. ATF4: activating transcription factor 4, GCN2: general control non-derepressible-2, eif2α: eukaryotic initiation factor 2α, KEAP1: Kelch-like ECH associated protein-1, NRF2: nuclear factor erythroid 2-related factor 2, p53: tumor protein p53, ATF3: activating transcription factor 3, BAP1: BRCA1 associated protein-1, PRC1: polycomb repressive complex 1, USP7: ubiquitin-specific-processing protease 7, SWI/SNF: SWItch/sucrose non-fermentable modeling complex, OTUB1: OTU deubiquitinase, ubiquitin aldehyde binding 1, mTORC1: mechanistic target of rapamycin complex 1, mTORC2: mechanistic target of rapamaycin complex 2
Figure 3
Figure 3
SLC7A11 promotes tumor development through both ferroptosis-dependent and -independent mechanisms. SLC7A11 promotes tumor development partly through detoxifying lipid peroxides and suppressing ferroptosis, which involves both ASCL4-dependent (via GPX4) and -independent (via ALOX12) pathways. Tumor suppressor proteins such as p53 and BAP1 inhibit tumorigenesis partly by suppressing SLC7A11 expression and promoting ferroptosis, while oncogenic KRAS and OTUB1 promote tumor development partly by promoting SLC7A11 levels and inhibiting ferroptosis. SLC7A11 can also promote tumorigenesis via pathways that are not dependent on its function to suppress ferroptosis. KRAS: Kirsten rat sarcoma viral oncogene homolog, OTUB1: OTU deubiquitinase, ubiquitin aldehyde binding 1, p53: tumor protein p53, BAP1: BRCA1 associated protein-1, ACSL4: Acyl-CoA synthetase long chain family member 4, GPX4: glutathione peroxidase 4, ALOX12: arachidonate 12-lipoxygenase
Figure 4
Figure 4
SLC7A11 regulates glucose and glutamine dependencies in cancer cells. (A) SLC7A11 functions to import extracellular cystine in exchange for intracellular glutamate. Extracellular glutamine is imported into the cell and converted to glutamate by Glutaminase. Subsequently, glutamate serves to fuel the TCA cycle via its conversion to α-ketoglutarate and acts as a precursor for GSH synthesis. The other arm of SLC7A11 transporter function imports extracellular cystine. Once imported into the cell, cystine is reduced to cysteine by the consumption of NADPH. Cysteine then serves as the rate limiting precursor for GSH synthesis, and GSH suppresses ROS. NADPH is mainly supplied from glucose via the PPP. Consequently, an imbalance in this metabolic network leads to specific metabolic dependencies in SLC7A11high cancer cells. (B and C) Glutamine dependency: In SLC7A11high cancer cells, increased glutamate export results in a partial depletion of intracellular glutamate that can feed into the TCA cycle. This pushes SLC7A11high cancer cells to uptake more glutamine and activates glutaminase to promote glutamine conversion to glutamate, resulting in glutamine dependency (B). When SLC7A11high cancer cells (with increased glutamate export) are challenged with low glutamine availability, intracellular glutamate is inadequate to fuel the TCA cycle, resulting in anaplesrosis defect and cell growth arrest (C). (D and E) Glucose dependency: In SLC7A11high cancer cells, large amount of extracellular cystine is imported into the cell. Due to its low solubility, buildup of intracellular cystine is likely toxic, forcing cells to quickly reducing cystine to much more soluble cysteine in the cytosol. Because this reaction requires NADPH and cytosolic NADPH is mainly supplied from glucose via the PPP, SLC7A11high cancer cells exhibit glucose-PPP dependency. (D) Limiting glucose availability in SLC7A11high cancer cells leads to NADPH depletion, accumulation of intracellular cystine and other disulfide molecules resulting in disulfide stress and rapid cell death (E). GSH: reduced glutathione, PPP: pentose phosphate pathway, TCA cycle: tricarboxylic acid cycle, αKG: α-ketoglutarate
Figure 5
Figure 5
Therapeutic strategies to target SLC7A11 in cancer. The antiporter function of SLC7A11 offers several strategies for therapeutic targeting. (1) Direct blocking of SLC7A11 cystine transporter activity using its inhibitors such as erastin, IKE, sulfasalazine, sorafenib, and HG106. These drugs inhibit cystine uptake by SLC7A11, thereby inducing lipid peroxidation and ferroptotic cell death. (2) Targeting glucose dependency in SLC7A11high cancer cells by inhibiting glucose uptake using GLUT inhibitors. Decreased glucose availability in in SLC7A11high cancer cells induce disulfide stress, leading to rapid cell death. (3) Targeting glutamine dependency in SLC7A11high cancer cells by using glutaminase inhibitors such as CB-839. Glutaminase inhibition decreases glutamate-derived anaplerosis and induces cell growth arrest in SLC7A11high cancer cells. IKE: imidazole ketone erastin, GLUT: glucose transporter
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