Role of SLC7A11 in Cancer Metabolism: History
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Contributor:
Jaewang Lee
,
Jong-Lyel Roh

Solute carrier family 7 member 11 (SLC7A11) is a cell transmembrane protein composing the light chain of system xc−, transporting extracellular cystine into cells for cysteine production and glutathione (GSH) biosynthesis. SLC7A11 is a critical gateway for redox homeostasis by maintaining the cellular levels of GSH that counter cellular oxidative stress and suppress ferroptosis. SLC7A11 is overexpressed in various human cancers and regulates tumor development, proliferation, metastasis, microenvironment, and treatment resistance.

  • SLC7A11
  • cysteine
  • ferroptosis
  • redox
  • cancer

1. Role of SLC7A11 Linking Cysteine Redox Signaling to Cancer Metabolism

Cysteine is mainly produced by cystine uptake into cells through the solute carrier family 7 member 11 (SLC7A11) subunit of system xc−. Cancer cells critically depend on the intracellular uptake of amino acids from their microenvironments, and extracellular cystine uptake is required for cancer growth and progression [1]. Cancer cells are hallmarked by resistance from cell death, most notably apoptosis [2]. The characteristics make precancerous cells or cancer cells exposed to metabolic stress or nutritional deficiencies resistant to apoptosis or other types of cell death. Recent studies have unraveled that ferroptosis, similar to apoptosis, is actively involved in the mechanisms of inhibiting tumorigenesis in changing microenvironments [3]. SLC7A11 is involved in antioxidant defense and cellular redox homeostasis through cysteine and glutathione (GSH) production and has emerged as a central hub linking its ferroptosis suppression to tumor initiation and progression.

1.1. SLC7A11 Promotes Tumorigenesis via Inhibiting Ferroptosis

Cellular redox balance plays a critical role in cellular transformation and tumorigenesis through redox homeostasis between mutagenic ROS production and tight control by antioxidant programs responsive to cellular stressors [4][5]. Enhanced intracellular GSH biosynthesis by SLC7A11 overexpression is essential for oncogenic RAS transformation by protecting cells from oxidative stress and cell death [6]. Transcriptional upregulation of SLC7A11 results from the ETS-1 transcription factor downstream of the RAS-RAF-MEK-ERK signaling cascade, directly transactivating the SLC7A11 promoter in synergy with ATF4. Notably, genetic depletion or pharmacological inhibition of SLC7A11 induces synthetic lethality in KRAS-mutant lung adenocarcinoma, highlighting SLC7A11 as a potential therapeutic target for RAS-driven tumors [7]. Interestingly, sulfasalazine and HG106 induce the selective inhibition of SLC7A11, but both drugs exhibit different types of cell death by increasing cellular oxidative stress, namely ferroptosis and apoptosis, respectively. This suggests that SLC7A11 may have different functions independent of ferroptosis in promoting tumor development, such as apoptosis and other non-ferroptotic cell death. OTUB1 deubiquitinates and stabilizes the SLC7A11 protein by direct interaction [8]. OTUB1 overexpression is frequently found in various human cancers, which maintains high expression of SLC7A11 in cancer cells by posttranslational regulation of OTUB1.
De-repression of SLC7A11 also promotes tumor development partly via inhibiting ferroptosis, e.g., genetic mutations or deletions of tumor suppressor p53 or BAP1. p53 is the most frequently mutated tumor suppressor in human cancers, suggesting that the p53-induced transcriptional repression of SLC7A11 plays an important role in p53-mediated tumor suppression [9]. The p53 mutation at three acetylation sites (K117R+K161R+K162R, 3KR mutant) loses its ability to induce cell cycle arrest, senescence, and apoptosis, yet still is capable of regulating ROS production and suppressing tumor formation [10]. The preserved function of tumor suppression in the p53 3KR mutant has been later unraveled, partly by repressing SLC7A11 expression [11]. However, the additional mutation (K98R) in the p53 3KR mutant markedly abolishes the ability of p53 to suppress tumor formation by repressing SLC7A11 expression and inducing ferroptosis in cancer cells [12]. Arachidonate 12-lipoxygenase (ALOX12) also plays a critical role in p53-mediated ferroptosis [13]. ALOX12 mediates polyunsaturated fatty acid (PUFA) peroxidation and ferroptosis independently of the canonical ferroptosis pathway through the GPX4 and acyl-CoA synthetase long-chain family member 4 (ACSL4) axis. Mechanistically, SLC7A11 interacts with ALOX12, which suppresses PUFA peroxidation and ferroptosis. ALOX12 mutations in human cancers promote tumorigenesis by abrogating its ability to oxygenate PUFAs and induce ferroptosis. BAP1 is another tumor suppressor repressing SLC7A11 transcription through H2A histone ubiquitination, which inhibits cystine uptake and GSH biosynthesis, and promotes ferroptosis [14]. As BAP1 is frequently mutated in human cancers, BAP1 mutation contributes to tumor development by abrogating its ability to suppress the SLC7A11 expression and induce ferroptosis [15].

1.2. SLC7A11 Promotes Immune Evasion, Invasion, and Metastasis in Human Cancers

In the tumor microenvironment, SLC7A11 is involved in tumor survival and proliferation through the interaction between immune cells and tumor cells. Interferon gamma (IFN-γ) secreted by CD8+ cytotoxic T cells promotes lipid peroxidation and ferroptosis by inhibiting the expression of SLC3A2 and SLC7A11, two subunits of system xc− in tumor cells [16]. Cysteine is an essential amino acid for T-cell activation. T-cells lacking SLC7A11 or cystathionases rely on neutral amino acid transporters to release cysteine from APCs [17]. Cysteine export by APCs is reduced by the presence of MDSCs, limiting antitumor immunity by T-cell activation [18]. In glioma cells, an increase in extracellular glutamate caused by overexpression of SLC7A11 impairs cytotoxic T-cell activation and promotes regulatory T (Treg)-cell proliferation, leading to intratumoral immunosuppression [19][20]. The altered cancer metabolism through overexpression of SLC7A11 promotes immune evasion of glioblastoma multiforme (GBM) through dysfunction of T cell activation. Antitumor immunity caused by T cell activation is also diminished by CD36-mediated uptake of fatty acids in tumor-infiltrating CD8+ T cells that induces lipid peroxidation and ferroptosis of the cells [21]. Additionally, SLC7A11 has a potential role in cancer-associated fibroblasts (CAFs) or vascular remodeling. SLC7A11 is highly expressed in CAFs, enabling tumor cells to protect against exogenous oxidative stress [22]. In human cancer, ATF4 promotes the transcription of genes involved in stress response, including SLC7A11, to increase tumor angiogenesis and shape blood vessel architecture [23].
Increased expression of SLC7A11 and/or CD44 is found in various human cancers and is closely associated with tumor invasion, lymph node metastasis, recurrence, and poor prognosis [24][25]. SLC7A11-mediated glutamate release promotes glioma cell infiltration and could be blocked by xCT inhibitors such as sulfasalazine and (S)-4-carboxyphenylglycine [26]. SLC7A11 expression is also involved in the invasion and metastasis of melanoma, and loss of SLC7A11 can inhibit melanoma metastasis in vivo [27]. PDAC has a highly metastatic potential with few effective therapeutic options. Mitochondrial calcium uniporter (MCU) can promote tumor metastasis by activating the Keap1–Nrf2–SLC7A11 axis [28]. SLC7A11 inhibition in MCU-high PDAC effectively induces tumor regression and abolishes MCU-driven metastasis. In addition, CAF highly depends on cystine uptake and GSH synthesis via SLC7A11 expression in PDAC. Therefore, targeting SLC7A11 in both compartments of PDAC stromal and tumor cells could be a more effective treatment approach [22].
SLC7A11-mediated extracellular glutamate secretion can also promote the intrinsic invasiveness of cancer cells. Glutamate release by SLC7A11 promotes tumor invasion through the upregulation of membrane type 1 metalloprotease and basement membrane disruption in breast cancer cells [29]. Glutamate excretion by IL-1β-induced SLC7A11 overexpression can also promote hepatoma metastasis through the upregulation of programmed death ligand 1 (PD-L1) and colony-stimulating factor 1 (CSF1) [30]. Pharmacological interference of glutamate release from tumor cells can limit host bone response and impairs bone metastasis of cancer cells [31].

1.3. SLC7A11 Induces Nutrient Dependency and Metabolic Vulnerability in Cancer

Altered energy metabolism is a hallmark of cancer that can be an effective treatment target [32]. Tumors are metabolically diverse by reprogramming pathways for nutrient acquisition. A better understanding and detection of tumor metabolic reprogramming has been increasingly supported as a new strategy to treat human cancer. Cancer cells promote tumor growth and proliferation through amino acid metabolism reprogramming. Tumor cells maintain the redox balance and cell survival by developing antioxidant systems to control the increased cellular levels of ROS along with their proliferation [4][5].
As a major antioxidant, GSH biosynthesis requires cysteine. Cancer cells import a large amount of cystine into the cell through high levels of SLC7A11 expression (SLC7A11high) and quickly reduce highly insoluble cystine to more soluble cysteine. This reaction requires a cellular NADPH pool mainly drained from the glycolysis–pentose phosphate pathway [33]. Therefore, cancer cells with SLC7A11high are highly dependent on this pathway and render such cells susceptible to limiting glucose supply [34][35]. Co-targeting glucose transporter type 1 (GLUT1) and GSH biosynthesis can induce NADPH depletion, marked accumulation of cystine and other disulfide molecules, and ROS accumulation, leading to the synthetic lethality of SLC7A11high tumor cells [36][37]. However, SLC7A11 knockdown or pharmacological inhibition by sulfasalazine in SLC7A11high cancer cells reduces cellular ROS levels and cell death induced by glucose deprivation [38]. This suggests that cellular ROS following glucose deprivation plays a critical role in SLC7A11-dependent cancer cell death. Additionally, high cell density in glioma cells promotes lysosomal degradation of SLC7A11, which may enable metabolic adaptation and cell survival [39].
SLC7A11 simultaneously imports cystine and exports glutamate at a 1:1 ratio. SLC7A11-mediated glutamate transport results in a deficiency of the intracellular glutamate-α-KG pool, requiring more glutamine uptake. This affects the nutritional dependence of cancer cells through glutamine anaplerosis and glutaminase (GLS) [40]. Cancer cells in SLC7A11high or cystine-rich conditions respond sensitively to glutamine analogs or glutaminolysis inhibitors that inhibit glutamine anaplerosis to the TCA cycle [41]. However, the upregulation of SLC7A11 antagonizes glutamine metabolism and restricts nutrient flexibility despite the cellular need for antioxidant defense [42]. Therefore, cancer cells reprogram their amino acid metabolism for adaptation to the changing microenvironment of nutrition. mTORC2 is a critical regulator of amino acid metabolism in cancer and can inhibit the activity of SLC7A11 by direct phosphorylation at serine 26 [43]. In an environment lacking micronutrient levels, cancer cells can regulate the function of SLC7A11 by mTORC2-mediated phosphorylation to protect themselves from cellular stress that facilitates increasing glutamate efflux and cystine uptake [43].
Cancer cells with SLC7A11high highly depend on specific amino acids, such as glucose and glutamine, which may force the establishment of a novel therapeutic strategy to target cancer-specific metabolic vulnerabilities. In SLC7A11high GBM cells, glucose restriction decreases mismatch repair genes and increases double-strand breaks, making cancer cells more susceptible to radiation therapy [44]. CD44v-expressing stem-like head and neck squamous cell carcinoma (HNSCC) cells retain metabolic reprogramming toward increased glutaminolysis, which renders the cells more sensitive to xCT inhibitors with the combination of glutamate dehydrogenase (GDH) inhibition [45]. However, cystine starvation could rescue glucose starvation-induced cell death in SLC7A11high cancer cells and render such cells less susceptible to ferroptosis induced by SLC7A11 inhibition [35]. In SLC7A11high cancer cells, the additional supply of cysteine, such as N-acetyl cysteine (NAC), could rescue the cells from glucose starvation but not from glutamine deprivation [35][46]. Therefore, it is necessary to further underpin the mechanistic understanding of nutrient dependence in cancer cells with the SLC7A11high cellular phenotype.

1.4. SLC7A11 Has a Role in Cancer Therapeutic Resistance

SLC7A11 expression is closely related to treatment resistance through multiple pathways such as the antioxidant system, nutritional limitation, autophagy, and multidrug resistance in cancer cells. A previous study screened the potency of 1400 candidates, including amino acid analogs, L-alanosine, and geldanamycin, with anticancer effects in 60 human cancer cell lines [47]. SLC7A11 mediated cellular uptake of L-alanosine in cancer cells and conferred chemoresistance to geldanamycin by supplying cystine for GSH biosynthesis. Therefore, the SLC7A11 expression of cancer cells can be an important target for predicting resistance to anticancer drugs and overcoming treatment resistance.
The cell adhesion molecule CD44v interacts with SLC7A11 and stabilizes the protein in the plasma membrane, thus facilitating cystine uptake into cells [8]. CD44v-mediated upregulation of SLC7A11 promotes cystine supply and GSH synthesis, thereby inducing anticancer drug resistance in cancer cells [48]. CD44v expression is associated with 5-fluorouracil resistance in gastric cancer cells and may be abolished by SLC7A11 inhibition [49]. In addition, SLC7A11 inhibition induces selective cell death in CD44v-expressing HNSCC that are intrinsically resistant to EGFR-targeted therapy [50]. High CD44v and SLC7A11 expression are closely associated with the resistance to cisplatin in liver and bladder cancers, and sulfasalazine can eradicate the chemoresistant cancer cells [51][52].
Even after chemotherapy or radiotherapy, some cancer cells upregulate the expression of SLC7A11 to resist oxidative stress, inhibit cell death, and develop treatment resistance. Nrf2 and SLC7A11 are overexpressed in esophageal cancers, contributing to resistance to radiation and ferroptosis [53]. Enhanced expression of SLC7A11 is also found in GBM cells, partly due to the activation of Nrf2 [54]. An increase in cellular ROS by gene knockdown or pharmacological inhibitors of SLC7A11 leads to a synergistic effect in antitumor therapies. In CD133-positive hepatocellular carcinoma cells, the antioxidant defense systems against ROS are enhanced and play a central role in treatment resistance [55]. Sulfasalazine may improve the effectiveness of anticancer therapies by impairing the ROS defense system.
Conversely, a recent study showed that low expression of SLC7A11 was associated with resistance to paclitaxel and a low survival rate in ovarian cancer patients. Low expression of SLC7A11 was found in 90 drug-resistant ovarian cancer cell tissues, resulting from that, SLC7A11 strongly regulated cell autophagy as a competing endogenous RNA [56]. The multidrug-resistant protein P-glycoprotein (P-gp) is one of the most important defense mechanisms for cancer cell survival against anticancer drugs. Low regulation of SLC7A11 or cystine deprivation induces ROS-induced overexpression of P-gp in breast cancer cells and drug resistance [57]. SLC7A11 overexpression or cystine supplementation strongly reduces the expression and activity of P-gp. Cystine supply or NAC treatment renders drug-resistant lung cancer cells more sensitive to anticancer drugs [58]. This suggests that ROS and SLC7A11 are major factors affecting P-gp expression and function, and SLC7A11 is a potential target for regulating P-gp-related drug resistance.

2. Targeting SLC7A11 for Novel Cancer Therapeutics

Ferroptosis is a recent advance in oxidative-regulated cell death induced by the accumulation of iron-mediated lipid peroxidation [59]. Iron-loaded ROS production promotes PUFA peroxidation in ferroptosis. The Fenton reaction is the reaction between ferrous iron and hydrogen peroxide to form hydroxyl or peroxyl radicals that react with membrane lipids and rapidly propagate to neighboring PUFA-phospholipids [60]. Excessive lipid peroxidation disrupts the integrity of cell membranes, resulting in cell death [59]. Lipid peroxidation is driven by multiple iron-containing enzymes such as arachidonate lipoxygenases, e.g., 12/15-lipoxygenase, P450 oxidoreductase, and prostaglandin-endoperoxide synthase 2 [61]. The radical-trapping antioxidant systems protect cells from the excessive accumulation of cellular ROS by reducing ROS to H2O. GPX4 and SLC7A11 are the essential modulators of ferroptosis [62]. GPX4 is a major cellular antioxidant that reduces lipid hydroperoxides to lipid alcohols, resulting from the oxidation of GSH. SLC7A11 is a membrane protein that contributes to detoxifying lipid peroxidation by participating in the intracellular uptake of cystine for GSH production. GPX4 requires GSH as a cofactor that inhibits lipid peroxidation, and thereby the depletion of cysteine and GSH could inactivate the protective effect of GPX4 [63].
Ferroptosis was first coined by professor Stockwell and colleagues and is attracting attention as a novel treatment method for various human diseases [62][64]. In 2012, Dixon et al., screened lethal compounds triggering specific elimination of RAS-mutated cancer cells, which led to finding a novel form of non-apoptotic cell death, ferroptosis, that was morphologically, biochemically, and genetically distinct from other types of regulatory cell death [64]. Since then, the molecular regulation of ferroptosis has been elucidated through various model studies, and the biochemical characteristics of ferroptosis could be inhibited by iron chelators or lipophilic antioxidants [62][64]. The constitutive activity of SLC7A11 inhibits ferroptosis in various cells, while gene knockdown or pharmacological inhibition of SLC7A11 could induce ferroptosis. Notably, ferroptosis by SLC7A11 inhibition can be suppressed by β-mercaptoethanol, which reduces extracellular cystine to cysteine and promotes bypass of the system xc− [62]. Although SLC7A11 is overexpressed in various cancers, cancer cells maintain redox homeostasis by developing different antioxidant defenses to survive high levels of oxidative stress. Normal cells can replace SLC7A11 function by cystine uptake via additional transporters other than SLC7A11, or obtaining intracellular cysteine through de novo cysteine synthesis [65]. Cancer cells further develop the antioxidant systems necessary for oncogene adaption to induce overexpression of SLC7A11, which selectively targets cancer cells while minimizing adverse effects on normal cells [66]. SLC7A11 knockout, unlike GPX4 knockout, does not result in embryonic lethality and does not affect the development or phenotypes of the pancreas and other major organs [67][68]. Therefore, targeting SLC7A11 may be a promising therapeutic strategy to selectively treat cancer with minimal effects on normal tissues.
Several compounds have been identified as SLC7A11 inhibitors, including erastin, imidazole ketone erastin (IKE), sulfasalazine, and sorafenib [7][59]. These agents were characterized as class 1 ferroptosis inducers (FINs) capable of inducing ferroptosis by blocking cystine uptake of SLC7A11. Erastin is the most widely used class 1 FIN, which has been discovered to selectively eliminate cancer cells harboring the oncogenic mutant RAS [69]. However, erastin cannot be used in animal experiments or humans due to poor metabolic stability and low solubility in vivo [59]. IKE, an erastin analog with high metabolic stability and solubility, has nanomolar potency and suitability for testing ferroptosis in preclinical studies [70]. IKE treatment mimics the effects of cystine depletion, such as cystine starvation or system xc− inhibition, which is reversed by co-treatment with iron chelators, ferrostatin-1, or NAC in cancer cells. IKE could effectively suppress the growth of pancreatic cancers vulnerable to the cystine-deprived, hypoxic microenvironment in a genetically engineered mouse model of PDAC [66]. However, IKE was developed relatively recently and has not yet moved to the clinical trial stage in cancer patients. Sulfasalazine and sorafenib are currently being actively used in clinical patients for the treatment of arthritis and human cancers, respectively, under the approval of the U.S. Food and Drug Administration. Both drugs can suppress tumor growth by inhibiting the SLC7A11 transporter activity of SLC7A11 and ferroptosis in vivo [59][71][72]. HG106, recently known as a potent SLC7A11 inhibitor, also showed marked tumor suppression and prolonged survival in the preclinical mouse models of KRAS-mutated lung adenocarcinoma [7]. Recently, an engineered and pharmacologically optimized human cyst(e)inase enzyme could suppress tumor growth in PDAC, prostate, and breast cancer xenografts [66][73]. Systemic administration of cyst(e)inase depleted serum L-cysteine and L-cystine pools and doubled the median survival time of TCL1-Tg:p53-/- mice resembling chronic lymphocytic leukemia [73]. In summary, although the class 1 FIN agents have proven their effectiveness in numerous preclinical studies, the proof of concept has rarely been established in clinical trials in cancer patients. Therefore, it is urgent to develop more therapeutically effective and minimal side-effect SLC7A11 inhibitors and test them in rigorous preclinical models and clinical trials.

This entry is adapted from the peer-reviewed paper 10.3390/antiox11122444

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