IJMMInternational Journal of Molecular Medicine1107-37561791-244XD.A. Spandidos10.3892/ijmm.2024.5465ijmm-55-02-05465ReviewRole of solute carrier transporters in ovarian cancer (Review)QuaresimaBarbaraScicchitanoStefaniaFanielloMaria Concetta*MesuracaMaria*Department of Experimental and Clinical Medicine, 'Magna Graecia' University of Catanzaro, I-88100 Catanzaro, ItalyCorrespondence to: Dr Maria Mesuraca or Dr Barbara Quaresima, Department of Experimental and Clinical Medicine, 'Magna Graecia' University of Catanzaro, Viale Europa, I-88100 Catanzaro, Italy, E-mail: mes@unicz.it, E-mail: quaresi@unicz.it
Solute carrier (SLC) transporters are involved in various biological processes associated with metabolic reprogramming and cancer, supporting the increased requirement of nutrients and energy. Over the past decade, there have been significant advancements in understanding the expression and function of SLCs in ovarian cancer (OC). This gynecological condition has a high mortality rate and limited treatment options; thus, early diagnosis remains a target clinically. OC exhibits complexity and heterogeneity, resulting in different clinical characteristics, resistance to chemotherapy drugs and poor prognosis. Additionally, SLCs have a different expression pattern between healthy and tumor tissue, and consequently, their inhibition or activation could modify signaling pathways involved in the tumor growth process, such as cell proliferation, apoptosis and drug accumulation. The present review aims to consolidate current data to provide a comprehensive understanding of the potential importance of SLCs in OC. Additionally, it seeks to offer guidance for further research on utilizing SLCs as prognostic biomarkers and therapeutic targets.
Key wordssolute carriertransporterovarian cancersignaling pathwaystumorigenesisdrug resistanceTerritorial R&D Leaders2021/3277Technologies for climate change adaptation and quality of life improvementECS0000009This work was supported by the Next Generation EU - Italian NRRP, Mission 4, Component 2, Investment 1.5, call for the creation and strengthening of 'Innovation Ecosystems', building 'Territorial R&D Leaders' (Directorial Decree n. 2021/3277) - project Tech4You - Technologies for climate change adaptation and quality of life improvement (project no. ECS0000009).Introduction
Transporters are membrane proteins that facilitate the movement of various substances such as nutrients, neurotransmitters, ions, metabolites and drugs, and are involved in important biological processes including the regulation of cell signaling and the organization of cellular organelles (1). Originally, these membrane proteins were categorized as ATP-independent transporter proteins, but in 2004 they were classified into two major superfamilies: The ATP-binding cassette (ABC) and solute carrier (SLC) families (2-4).
Membrane transporters SLCs, which are more numerous than ABCs, play a crucial role in facilitating communication between the cell and its environment. Genetic variants in the SLC family have been associated with various diseases, including neurological or metabolic disorders and cancer (5,6). Despite their biological importance, SLCs are among the most understudied class of proteins, with >455 membrane-bound proteins classified into 66 families, for this reason, numerous aspects of their biology remain unknown (7).
There have been significant advances in the structural biology of membrane proteins, which have greatly improved the understanding of molecular-level transport (6). SLC transporters are an extremely diverse family of membrane proteins. The most common structural classes in human SLCs are the LeuT-like fold leucine transporter (such as SLC6) and the Major Facilitator Superfamily (such as SLC2) (7-10). The diversity of SLC proteins is determined by the specificity of the substrate, as well as the different regulatory properties and tissue- and cell-type-specific metabolic requirements (11-13).
Ovarian cancer (OC) is a gynecological pathology with a high mortality rate, often diagnosed at an advanced stage, leading to a poor prognosis (14). The main response at the onset of the disease is instrumental screening followed by surgical ablation. However, therapeutic options are limited, especially in relapses, which often become resistant to chemotherapy drugs (15,16). The complexity and heterogeneity of OC can result from the uncontrolled proliferation of epithelial, germ or stromal cells, leading to the development of malignant tumors with differences in epidemiology, clinical characteristics, response to chemotherapy and prognosis (16).
In recent decades, it has been widely demonstrated that hereditary or acquired genetic alterations have an important role in the etiology of OC. For instance, BRCA1 and BRCA2 mutations have long been associated with an increased risk of developing breast cancer or OC (16-18). Additionally, genetic variants in other genes such as RAD51C, RAD51D and PALB2, as well as in MLH1, MSH2 and MSH6 genes, have been identified in 15-20% of OC cases (19,20). This knowledge allows us to identify and screen individuals with a greater probability of developing certain tumor syndromes and to activate counseling and tumor surveillance, particularly when the risk assessment is correlated with a previous family history (15).
Recent studies have shown that changes in gene expression levels can significantly impact patient survival and their response to chemotherapy. Additionally, identifying the molecular pathways and biomarkers involved in tumor growth, proliferation and migration in OC is crucial in fighting this type of tumor. Transcription factors that modulate regulatory genes involved in epithelial-mesenchymal transition (EMT) have been recently identified (21-23). Chen et al (23) demonstrated that upregulation of RUNX family transcription factor 1 (RUNX1) is linked to tumor progression and overall survival (OS), while its knockdown showed a significant decrease in the capacity for proliferation and invasion in OC cell lines. Additionally, RUNX1 knockdown reduces EMT through the EGFR/AKT/STAT3 pathway and promotes apoptosis via the FOXO1-Bcl2 axis in OC cell lines. Furthermore, lower expression of RUNX1 improves sensitivity to chemotherapeutics in patients, as observed in short hairpin-RUNX1 ovarian cell lines, suggesting a synergistic effect (23). Moreover, not only genes but also mutation types can play a role in different sensitivities to chemotherapy treatments, as shown by certain studies reporting a different sensitivity to PARP inhibitors, depending on the type and location of BRCA1/2 mutations or in other genes (24).
An increasing body of information has been obtained regarding the role played by ABC and SLC transporters in the development of multidrug resistance (MDR). This information has been gathered from gene expression analysis in OC cell lines and human primary tumors using microarray techniques (25,26). These analyses have highlighted changes in the expression patterns of transporters and their involvement in tumor progression and the development of resistance to chemotherapy drugs (27). Teng et al (28) have demonstrated that ABCC1 or ABCG2 overexpression compromised the drug response in OC cell lines, decreasing their cytotoxic capacity. It was also observed that the knockout of the singular genes or competition by specific inhibitors reversed the resistance process since they significantly reduced the efflux of the anticancer drug from the cells (28).
In cancer, including OC, SLC transporters are dysregulated. This allows tumors to obtain more energy and nutrients giving them an advantage in supporting their metabolic needs (29,30). Additionally, some SLCs can contribute to drug resistance by interfering with the cell death processes and various signaling pathways that influence proliferative capacity and tumor progression (3,31). Therefore, the present review aims to summarize the current knowledge regarding the involvement of SLCs in OC and how they may impact the pharmacological response.
SLCs expressed in OC
SLC transporters are differentially expressed in various cell types and tissues. Dysregulation of these transporters is linked to metabolic diseases and tumorigenesis. While a number of studies have explored the role of SLCs in different types of tumors, there has been insufficient research focusing on their involvement in OC (4-6). The SLCs associated with this form of cancer exhibit different transport mechanisms (Fig. 1). The localization and further information on the transporters reported in the present review are listed in Table I.
SLC1A5
The expression levels of SLC proteins differ between healthy and cancer cells. Amino acid transporters, such as SLC1A5 (also known as ASCT2), play a crucial role in cancer metabolism by supporting the increased energy demand for rapid cellular growth. SLC1A5 is involved in the uptake of amino acids (Ala, Ser, Cys and Gln), and downregulation of Gln metabolism has been found to inhibit cell proliferation in various tumors, including OC (3,32,33). In OC tissues, SLC1A5 is significantly upregulated and has been linked to clinical factors and prognosis (32,33). In epithelial OC (EOC), high expression of both SLC1A5 and phosphorylated (p-)mTOR has been observed, and the mTOR signaling pathway is known to promote tumor cell proliferation through Gln metabolism. Furthermore, the co-expression of SLC1A5 and p-mTOR has been associated with poor OS, indicating a synergistic effect on the growth and development of EOC (33). Recent studies have also identified specific microRNAs (miRNAs) that can modulate SLC1A5 gene expression in OC. For instance, upregulation of miR-122-5p has been shown to regulate SLC1A5 expression by downregulating circular RNA (circ)_0072995, thereby affecting cell growth, apoptosis and invasion. This study reported the role of the cir_0072995/miR-122-5p/SLC1A5 axis in OC tumorigenesis (34). Another study highlighted a similar mechanism of SLC1A5 regulation through the circ_0025033/hsa_miR-370-3p axis (35). Additionally, a new axis has been identified between claudin-4, SLC1A5 and SLC7A5. Claudin-4 is a gene that encodes a tight junctional protein involved in modulating genomic instability and is associated with worse patient outcomes in OC (36). This axis plays a critical role in amino acid transport through the plasma membrane, contributing to increased OC aggressiveness (36).
SLC3A2
The SLC3A2 gene, also known as 4F2hc or CD98, encodes for a type II transmembrane glycoprotein that can bind to SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 and SLC7A11, forming heterodimeric transporters expressed in different tissues (37,38). In particular, the interaction between SLC3A2 and SLC7A11 (also known as xCT) or SLC7A5 [also known as L-type amino acid transporter (LAT) 1] is involved in an exchange that imports Cystine and essential amino acids (EAAs) and exports Glu and Gln, respectively (37). In addition to the cell membrane, the heterodimeric complex formed by SLC3A2 and SLC7A5 is present in the lysosomal membrane, where SLC3A2/SLC7A5 binds to lysosome associated protein transmembrane 4B (LAPTM4b) promoting Leu and other EAAs to influx into lysosomes, which is required for mTORC1 activation via V-ATPase (38).
Several studies have demonstrated that SLC3A2 expression and its partners are dysregulated in a number of cancer types, where this protein is involved in different stages of tumor development (39-41). In OC, SLC3A2 upregulation supports chemotherapy treatment and decreases tumor masses (40,41). A recent bioinformatics analysis study demonstrated the association of the SLC3A2-CD147 complex as a potential risk factor in patients with OC (42).
SLC4A11
The SLC4 family includes 10 proteins involved in the homeostasis control of intracellular pH (pHi) that mediate Cl−/HCO3− and Na+/HCO3− membrane cotransport. A divergent role has been shown for the SLC4A11 protein that instead mediates the Na+/OH− and NH4+ exchange (43). In OC cells, the metabolic changes typical of the neoplastic environment induce upregulation of H+ transporters with consequent extracellular acidification, supporting tumor invasion and metastasis (43-46). It has been demonstrated that SLC4A11 upregulation is more evident in OC tissues than in normal tissues, particularly in patients with metastasis vs. those without metastasis. Moreover, higher SLC4A11 expression has been linked to poor OS. Dataset analysis of the SLC4A11 gene regulation highlighted that regulation depends on methylation and DNA amplification processes (43).
SLC7 family
The SLC7 family genes mediate amino acid transport, and their dysregulation is linked to a number of human diseases, different stages of tumor development and the drug resistance of different cancer types (47,48). The SLC7 family is divided into two subfamilies, namely the cationic amino acid (CAT) and LAT transporter families. The human CAT subfamily includes SLC7A1, SLC7A2, SLC7A3 and SLC7A4, while the LAT family comprises six proteins, SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 and SLC7A11 (3,49). To date, few studies have examined the role of SLCs in OC. However, some proteins of the SLC7 family, SLC7A2, SLC7A5 and SLC7A11, have been recognized to play critical roles in OC (38,47,50-54).
Different expression of SLC7 members was revealed in OC compared with normal tissue using the GEPIA dataset, which showed the upregulation of SLC7A1, SLC7A4 and SLC7A7, and the downregulation of SLC7A2 and SLC7A8 (47). A recent study by Gong et al (47) showed that SLC7A1 upregulation was correlated with poor OS in OC, as was reported in different tumor types where high SLC7A1 expression was also involved in the tumor-infiltrating immune microenvironment (48). In addition, patients with OC and high SLC7A1 levels develop drug resistance and a higher probability of recurrence (47,49). Another recent study by Circle-seq revealed that some upregulated genes, including SLC7A1, were associated with OC prognosis and were able to influence the cell adhesion and extracellular matrix-receptor interaction pathways (55).
Unlike SLC7A1, SLC7A2 is downregulated in various tumor types and induces tumor proliferation and resistance to chemotherapy drugs (48). Moreover, in an OC datasets analysis, Sun et al (50) observed that the SLC7A2 expression levels were significantly lower in younger individuals compared with patients ≥60 years old. In addition, this study also demonstrated the role of SLC7A2 in tumor progression by functional experiments in cancer cell lines. The results highlighted that SLC7A2 interferes with apoptosis, signaling pathways and drug resistance. Further SLC7A2 knockdown experiments showed an increased capacity for cell invasion and migration as well as elevated levels of EMT protein markers, such as N-cadherin and vimentin, in OC cell lines (50).
Numerous studies have shown that SLC7A5, also known as LAT1, is upregulated in several OC cell lines and primary tumors. In patients with OC, elevated levels of LAT1 have been correlated with tumor growth, angiogenesis and poor survival rates (32,56-58). A recent study using immunohistochemical analysis demonstrated that SLC7A5 upregulation is associated with certain histological subtypes, such as ovarian clear cell carcinoma (OCCC) (59). It was also previously shown that high SLC7A5 expression is correlated with chemoresistance only in CCC histological sub-types (58). SLC7A5 interacts with SLC3A2 to form a heterodimeric amino acid transporter and is involved in Leu uptake into lysosomes, mediating the interaction with LAPTM4b to activate the mTORC1 complex, as aforementioned (38). A recent study of OCCC demonstrated that inhibiting SLC7A5, which suppresses Leu entry, reduced cellular growth via the mTOR pathway (60). As aforementioned, the claudin-4/SLC1A5/SLC7A5 axis plays a critical role in decreasing patient survival, contributing to increased tumor aggressiveness (36).
The role of SLC7A6 has been investigated in the A2780 and A2780/cisplatin (CDDP) EOC cell lines using dataset analysis. This analysis highlighted an increased expression of CircSLC7A6 in A2780/CDDP cells, which was correlated with SLC7A6 upregulation and miR-2682-5p downregulation. Moreover, the CircSLC7A6/miR-26825p/SLC7A6 axis has been confirmed through CircSLC7A6 silencing experiments, revealing a direct decrease of SLC7A6 and an increased expression of miR-2682-5p (61). In addition, Li et al (61) reported a synergistic anti-proliferative and pro-apoptotic capacity of CDDP and baicalein when CircSLC7A6 was knocked down in A2780/CDDP cells.
SLC7A11 is the functional subunit of the Xc-system, which targets the exchange of L-Cystine and L-Glu across the plasma membrane (48). Numerous studies have highlighted the role of SLC7A11 in cancer biology (48,62-64). Altered expression of the SLC7A11 gene can regulate cell apoptosis, ferroptosis and autophagy in different types of cancer (54,65,66). The Cystine/Glu transport mediated by SLC7A11 promotes glutathione (GSH) biosynthesis, decreases reactive oxygen species (ROS) levels and protects cells from lipid peroxidation, as well as playing a role in metabolism, cell proliferation and drug resistance (67). In OC, the regulation of SLC7A11 has been the subject of much research and has sparked some controversy. One study indicated that high levels of SLC7A11 in patients with OC were linked to a favorable prognosis, while another study suggested that SLC7A11 was a poor prognostic factor and a potential therapeutic target associated with platinum resistance (53,68). Additionally, low expression of SLC7A11 inhibited the process of disulfidptosis and was associated with a poor prognosis. In this research, database analysis was conducted on a cohort of patients divided into two groups (worse and improved prognosis) and it was found that high expression of a gene set, which included SLC7A11, was correlated with the group showing improved prognosis (69). Previous dataset analyses have reported that the downregulation of SLC7A11 in drug-resistant OC tissues and paclitaxel-resistant cell lines negatively modulated autophagy genes (STX17, UVRAG and RAB33B) through competing endogenous RNA interactions (54,70,71).
Numerous studies have shown that SLC7A11 is regulated by various factors and is involved in cell death processes, making it a therapeutic target in tumor progression (54,65). The high expression levels of SLC7A11, determined through CCAAT enhancer binding protein γ (CEBPG)-mediated transcriptional control, inhibited ferroptosis and promoted ovarian tumor growth in in vivo experiments. These results were confirmed by CEBPG knockdown, which reduced ovarian tumor cell proliferation both in vitro and in vivo. Additionally, upregulation of CEBPG and SLC7A11 is associated with poor outcomes in patients with OC (54,72). Similarly, Ogiwara et al (73) demonstrated that, in AT-rich interaction domain 1A-deficient OC cell lines, decreased SLC7A11 protein expression led to low GSH levels, inducing cell vulnerability to drugs targeting glutamate-cysteine ligase synthetase catalytic subunit (GCLC). The inhibition of GSH/GCLC leads to apoptosis by increasing ROS levels (73). SLC7A11 is also involved in ferroptosis through silencing STEAP3, which reduces the expression levels of this Cystine/Glu transporter and inhibits the tumor growth of OC cells via the p53/SLC7A11 pathway (74). Another study showed that SNAI family transcriptional repressor 2 binds to the SLC7A11 gene promoter, decreasing its expression and inhibiting cell apoptosis and ferroptosis in OC cell lines (54,75). Additionally, the interaction between HRD1 and SLC7A11 induces the degradation of the transporter and suppresses tumorigenesis, promoting ferroptosis in OC (76).
Long non-coding (lnc)RNA and miRNA are important regulators of gene expression (77). Evidence indicates their involvement in both promoting and suppressing cancer in different tumor types, including OC. A recent study highlighted that lncRNA ADAMTS9-AS1 was upregulated in OC cells. Knocking down this lncRNA promoted ferroptosis, inhibiting cancer cell proliferation and migration. These effects were achieved via the miR587/SLC7A11 axis, suggesting that lncRNA ADAMTS9-AS1 plays a critical role in SLC7A11 expression (78).
In recent years, SLC7A11 has been identified as a biomarker involved in the mechanism of ferroptosis and in the alteration of a series of signaling pathways that can influence proliferative capacity and tumor progression (79,80). Moreover, bioinformatics analyses have been conducted to explore the tumor expression of SLC7A11 and evaluate its association with patient prognosis and survival in OC. This indicates SLC7A11 as an important factor in prognostic assessment (48,53,54,69).
SLC9A1
SLC9A1, also known as Na+/H+ exchanger 1 (NHE1), is a ubiquitous membrane protein involved in pHi control. In tumor cells, the metabolic switch leads to a decrease in pHi due to lactate production, which releases H+ ions in anaerobic conditions (46). Thus, to prevent hyper-acidification in the OC cell environment, transporters excluding protons from across the plasma membrane are upregulated to regulate the cellular pH (81,82). Increased NHE1 levels have been observed in EOC cell lines and tissues. Moreover, NHE1 upregulation has been correlated with shorter OS compared with individuals with lower NHE1 levels in patients with EOC (83). Through in vivo experiments, Szadvari et al (82) have reported that overexpression of the NHE1-Na+/Ca2+ exchanger 1 complex leads to alkalinization of pHi and prevents intracellular Na+ overload. However, alterations in NHE1 function, such as internalization or inhibition, result in cell hyper-acidification that induces apoptosis, which plays a critical role in cancer growth (46,82).
SLC12A5
The SLC12A5 gene, which encodes a potassium chloride cotransporter, is significantly expressed in various human cancer types and promotes the progression of prostate, bladder urothelial, hepatocellular and colorectal carcinoma (84-87), as well as other tumor types. There is an association between SLC12A5 and methyltransferases or DNA repair proteins (88). Research conducted by Yang et al (89) demonstrated the prognostic value of SLC12A5 in OC, where increased expression was associated with poor prognosis and survival. The authors also found a positive correlation between SLC12A5 protein upregulation and a more aggressive or invasive tumor phenotype. Gene amplification of SLC12A5 was detected in ~10.3% of OC cases, while no upregulation was observed in normal ovarian tissues.
SLC16A3
The SLC16A gene family consists of transporter proteins termed monocarboxylate transporters (MCTs), which are involved in metabolic processes and pH balance. This family includes SLCA16A1 (MCT1), SLCA16A7 (MCT2), SLCA16A8 (MCT3) and SLCA16A3 (MCT4) (90). Metabolic reprogramming and epigenetic modifications are well-known hallmarks of cancer, and they play a significant role in the uncontrolled growth and proliferation of tumor cells (91,92). Upregulation of SLC16A1 and SLC16A3 has been well-documented in the context of the tumor environment, due to their role in maximizing the capacity of lactate exporters, which helps prevent intracellular hyper-acidosis (93-95). RNA-sequencing (RNA-Seq) analysis revealed that SLC16A1 and SLC16A3 are upregulated in OC tissues compared with normal tissues. Additionally, SLC16A3 expression was found to be elevated in metastatic tissue and correlated with poor prognosis, suggesting it could be a potential therapeutic target (95).
In a previous study, it was found that certain SLC proteins, such as SLC16A3, can impact how cells respond to chemotherapy in both OC cell lines and tissues. These proteins can interfere with the movement of drugs across cell membranes. High expression of SLC16A3 was positively correlated with the MDR1 marker (96).
Furthermore, an analysis using Affymetrix Human Genome U219 microarrays in OC cell lines revealed the dysregulated expression of 32 SLCs. Specifically, 17 genes showed increased expression (such as SLC16A3, SLC2A9, SLC16A14, SLC38A4 and SLC39A8), while 15 genes showed decreased expression (such as SLC2A14, SLC6A15, SLC8A1 and SLC27A2). The study demonstrated that the significant upregulation of SLC16A3 contributed to drug resistance in cancer cells (97).
SLC31A1
SLC31A1, also known as CTR1, regulates copper homeostasis and acts as a transporter for platinum-based drugs (98). Regarding drug delivery, a study has linked SLC31A1 to the development of CDDP resistance in patients with OC (99). Various mechanisms including epigenetic changes, protein expression and post-translational modifications can influence drug resistance (25). Specifically, the transcriptional regulation of SLC31A1 in patients with CDDP-resistant EOC has been studied (100). Researchers using a CRISPR CAPTURE approach followed by mass spectrometry demonstrated that the transcription factor, ZNF711, targets the SCL31A1 promoter and recruits the demethylase, JHDM2A, in OC cell lines. This mechanism leads to increased activation of SLC31A1 transcription by removing the repressive transcriptional marker, H3K9me2. Additionally, the downregulation of this transcription factor has been linked to enhanced resistance to CDDP in patients with EOC by suppressing SLC31A1 transcription (100).
SLC34A2
The sodium-dependent phosphate transporter type 2b (NaPi2b; also known as SLC34A2 and NPT2) is a member of the SLC34 family, which also includes secondary transporters (such as NaPi2a and NaPi2c). The SLC34A2 gene encodes a protein involved in uptake control and in maintaining inorganic phosphate balance and is typically expressed in tissues under physiological conditions. However, upregulation of this protein has been observed in certain tumors, such as OC, leading to toxic accumulation of intracellular phosphate (101). Genome-scale CRISPR/Cas9 loss-of-function analysis in human cancer cell lines has revealed that inhibiting xenotropic and polytropic retrovirus receptor 1 (XPR1)-dependent phosphate efflux in SLC34A2-overexpressing cell lines can induce cancer cell death by disrupting inorganic phosphate balance (102). Analysis of datasets has shown high SLC34A2 expression in ovarian tumor tissues, which is correlated with reduced life expectancy (103).
SLC39 family
The availability of Zn2+ in cells depends on various physiological factors, including uptake and efflux facilitated by specific transporters with different tissue localizations. Changes in transporter expression and Zn availability are considered to be linked to certain diseases and can pose an additional risk factor for tumor development. The transporter families, SLC39 (ZIP) and SLC30 (ZnT), are responsible for the uptake and excretion of zinc ions, respectively. The storage of this ion is regulated by metallothioneins. ZIP transporters consist of four subfamilies with 14 different isoforms (ZIP1-14), characterized by 8 highly conserved transmembrane domains (104,105). ZnT transporters are divided into four groups with 6 transmembrane helices and a conserved zinc-binding site between helices II and V, where specific amino acids play a crucial role in determining metal specificity (105). Several studies have demonstrated an aberrant expression of SLC39A4 (ZIP4) in various types of tumors, including breast, pancreatic, ovarian carcinoma and hepatocarcinoma (106-109). RNA-seq data analyses have confirmed upregulation of ZIP4 in EOC tissues compared with normal tissues. This zinc transporter, activated by the lysophosphatic acid (LPA)/PPARγ axis, is upregulated in mice with more aggressive EOC, leading to spheroid formation and promoting cancer stem cell (CSC) activity and drug resistance to commonly used drugs such as CDDP or doxorubicin (DOX) (110). In high-grade serous ovary carcinoma, ZIP4 is upregulated compared with normal human tissues (111). Upregulation of this transporter mediates CSC-related cellular functions including tumor-forming capacity, the ability to increase cancer proliferation and invasion as well as conferring resistance to CDDP and DOX. ZIP4 is particularly associated with increased expression of CSC markers, such as aldehyde dehydrogenase 1 family member A1, SOX9, OCT4 and NOTCH3 (108). SLC39A13 (ZIP13) is involved in Zn release from the Golgi apparatus and vesicles, and its dysfunction is correlated with connective tissue disorders (104). Dataset analysis has shown a significant correlation between ZIP13 expression and poor OS and progression-free Survival (PFS) in human OC. Additionally, ZIP13 knockdown significantly reduced the migratory and invasive abilities of OC cells in vitro (112). In a metastasis model using BALB/c nude mice, OC cells with depleted ZIP13 via CRISPR/Cas9 technology, showed significantly decreased metastasis both in terms of tumor number and size compared with the control groups. This reduction in metastasis is considered to be due to the inhibition of the Src/focal adhesion kinase (FAK) signaling pathway (112).
SLC53A1
SLC53A1, also known as XPR1, is a gene involved in the efflux of inorganic phosphate. XPR1 variants determine the intracellular phosphate accumulation, leading to the formation of calcium phosphate precipitates (102). Recent research has shown high expression of XPR1 in OCCC cell lines. Experiments conducted in vitro and in mouse xenograft models using small interfering RNA-mediated knockdown of XPR1 in EOC cell lines have revealed its significant role in cellular proliferation and tumorigenicity in OC (113). Furthermore, as aforementioned, XPR1 plays a role in controlling phosphate homeostasis. Experiments in SLC34A2-overexpressing cell lines have shown that the loss of the XPR1 phosphate exporter inhibits cancer cell viability (102).
Therapeutic drugs and target genes
OC treatment options are determined by the stage of the disease. A number of studies have aimed to understand how to overcome drug resistance mechanisms (25,114). Various biological processes, including epigenetic changes, modifications in plasma membrane transport with drug accumulation and dysregulation of signaling pathways can lead to chemotherapeutic drugs resistance in OC (25). Recently, SLC transporters have gained recognition for their role in maintaining substrate availability and facilitating the influx or efflux of drugs across plasma membrane. Increasing knowledge underscores the importance of SLC transporters, such as SLC3A2 and the SLC7A family, in anticancer drug resistance (Table II) (38,41,49,50,60,61).
Most chemotherapeutic drugs function by inducing apoptotic processes in tumor cells. SLC7A11 is involved in various molecular pathways that are key in treating drug resistance in several tumors, including OC. A number of studies have suggested that the involvement of SLC7A11 can restore sensitivity to drugs and overcome chemoresistance to different antineoplastic molecules (54). Recent studies have shown that SLC7A11 can influence either cell proliferation or tumor progression (79,80). Treatment with the morpholine derivative, N-(4-morpholinomethylene) ethanesulfonamide (MESA), or the quinoline derivative Pt(II)-based complex, PtQ, in OC cells induced ferroptosis and inhibited the SLC7A11/glutathione peroxidase 4 (GPX4) signaling pathway. Specifically, treatment with MESA in OC cell lines led to cell death by increasing nuclear factor erythroid 2-related factor 2 (NRF2) expression and affecting ferroptosis-related signaling pathways (79,80).
Current advances in drugs design have introduced new inhibitory molecules representing a valid approach for regulating target genes. SLC9A1 plays a critical role in cancer growth, and a previous study in OC cells have shown that SLC9A1 inhibitors (such as Zoniporide and 5-N,N-hexamethylene amiloride) could support chemotherapeutic treatment to reduce proliferative capacity (46). As aforementioned, drug delivery experiments have shown that suppressing SLC31A1 expression impaired CDDP resistance in patients with EOC. Treatment with BIX-01294 (a diazepin-quinazolinamine derivative), a histone methyltransferase inhibitor, has been shown to increase the sensitivity of EOC cells to CDDP by removing the repressive transcriptional effects of SLC31A1 mediated by ZNF711 transcription factor and the demethylase, JHDM2A (100).
Targeted therapies have revolutionized the landscape of OC using highly selective monoclonal antibodies, and studies with a specific antibody-drug conjugates (ADCs) are underway (115). SLC34A2-targeting ADCs, LIFA (lifastuzumab vedotin) or UpRi (Upifitamab rilsodotin), have been used as a treatment for gynecological tumors. This approach combines the tumor-targeting ability of monoclonal antibodies with chemotherapy agents. Promising trials are underway in OC to improve health-related quality of life and treatment efficacy, particularly in terms of PFS, OS and other measures (101,116).
Altered expression of Zn transporters and their availability have been linked to various solid tumors and represent an additional risk factor for disease progression (104,105). Research has shown that upregulation of SLC39A4 is activated by the LPA/PPARγ axis, inducing resistance to drugs such as CDDP or DOX (110). SLC39A13 knockdown reduces migratory and invasive abilities of OC cells. In a BALB/c nude mice model injected with ZIP13-depleted OC cells, significantly decreased tumorigenesis through inhibition of the Src/FAK signaling pathway was observed (112). Table II reports the expression of known SLCs in OC correlated to target genes associated with cancer proliferation, survival and resistance to chemotherapy. Therefore, studying the different ways in which SLC transporters impact cancer cells and assessing the activation or inhibition of signaling pathways could be a crucial step in expediting the development of drugs to treat OC.
Conclusions
The present review discussed the involvement of SLC transporter proteins in OC and summarized the existing evidence regarding their role. While a number of SLCs are extensively studied in various types of cancer, their role in OC has not yet been fully explored. Various SLCs play a crucial role in tumor cells by supporting rapid growth and modifying the cellular microenvironment. Recent bioinformatics analysis of ovarian tumor tissues has revealed different expression levels of SLCs, highlighting their involvement in cancer progression and modifying drug sensitivity. The heterogeneity of SLC expression in various diseases and tumors including OC, and their dysregulation is also associated with tumor progression. However, as aforementioned, numerous SLCs in OC are still uncharacterized and poorly understood, leading to limited options for improving cancer cell response to chemotherapy drugs. Furthermore, early-stage OC diagnosis requires the identification of new potential biomarkers to predict response to chemotherapy drugs and improve the OC prognosis. Moreover, it is important to consider the long-term impact on the quality of life, as it may influence therapeutic treatment.
New strategies targeting SLCs through innovative immunotherapy may increase the therapeutic opportunities and improve the response to chemotherapeutic drugs for treating OC. In the last decade, multi-omics data analysis has provided valuable information that can support the understanding of clinical aspects (such as PFS and OS) and the expression of SLCs. Therefore, more focused studies are needed to identify a subset of genes, including SLC transporters, that are prognostically relevant. This is crucial to bridge the information gap between the dysregulation of molecular pathways, immunotherapy response and drug resistance linked to poor outcomes in OC.
Availability of data and materials
Not applicable.
Authors' contributions
BQ, MCF and MM conceived and designed the review. SS was responsible for acquisition and interpretation of the data. BQ, SS, MCF and MM drafted and edited the manuscript for publication and reviewed the literature. All authors read and approved the final version of the manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Authors' information
Barbara Quaresima: https://orcid.org/0000-0003-3462-624x; Stefania Scicchitano: https://orcid.org/0000-0002-3566-7214; Maria Concetta Faniello: https://orcid.org/0000-0001-6938-2754; Maria Mesuraca: https://orcid.org/0000-0002-5455-168X.
Acknowledgements
Not applicable.
ReferencesCésar-RazquinASnijderBFrappier-BrintonTIsserlinRGyimesiGBaiXReithmeierRAHepworthDHedigerMAEdwardsAMSuperti-FurgaGA call for systematic research on solute carriersCell16247887201510.1016/j.cell.2015.07.02226232220HedigerMARomeroMFPengJBRolfsATakanagaHBrufordEAThe ABCs of solute carriers: Physiological, pathological and therapeutic implications of human membrane transport proteinsIntroductionPflugers Arch447465468200410.1007/s00424-003-1192-yXiaRPengHFZhangXZhangHSComprehensive review of amino acid transporters as therapeutic targetsInt J Biol Macromol260Pt 2129646202410.1016/j.ijbiomac.2024.12964638272411NwosuZCSongMGdi MaglianoMPLyssiotisCAKimSENutrient transporters: connecting cancer metabolism to therapeutic opportunitiesOncogene42711724202310.1038/s41388-023-02593-x3673936410266237Vander HeidenMGCantleyLCThompsonCBUnderstanding the Warburg effect: the metabolic requirements of cell proliferationScience32410291033200910.1126/science.1160809194609982849637LinLYeeSWKimRBGiacominiKMSLC transporters as therapeutic targets: emerging opportunitiesNat Rev Drug Discov14543560201510.1038/nrd4626261117664698371SchlessingerAZatorskiNHutchinsonKColasCTargeting SLC transporters: Small molecules as modulators and therapeutic opportunitiesTrends Biochem Sci48801814202310.1016/j.tibs.2023.05.0113735545010525040DvorakVSuperti-FurgaGStructural and functional annotation of solute carrier transporters: Implication for drug discoveryExpert Opin Drug Discov1810991115202310.1080/17460441.2023.224476037563933XieTChiXHuangBYeFZhouQHuangJRational exploration of fold atlas for human solute carrier proteinsStructure3013211330.e5202210.1016/j.str.2022.05.01535700727PerlandEFredrikssonRClassification systems of secondary active transportersTrends Pharmacol Sci38305315201710.1016/j.tips.2016.11.008NishimuraMNaitoSTissue-specific mRNA expression profiles of human solute carrier transporter superfamiliesDrug Metab Pharmacokinet232244200810.2133/dmpk.23.2218305372MoriokaSPerryJSARaymondMHMedinaCBZhuYZhaoLSerbuleaVOnengut-GumuscuSLeitingerNKucenasSEfferocytosis induces a novel SLC program to promote glucose uptake and lactate releaseNature563714718201810.1038/s41586-018-0735-5304643436331005O'HaganSWright MuelasMDayPJLundbergEKellDBGeneGini: Assessment via the Gini Coefficient of Reference 'Housekeeping' genes and diverse human transporter expression profilesCell Syst6230244.e1201810.1016/j.cels.2018.01.003LiJLiJJiangWEffects of different surgical extents on prognosis of patients with malignant ovarian sex cord-stromal tumors: A retrospective cohort studySci Rep1422630202410.1038/s41598-024-67446-33934950511442459KostovSWatrowskiRKornovskiYDzhenkovDSlavchevSIvanovaYYordanovAHereditary gynecologic cancer syndromes-A narrative reviewOnco Targets Ther15381405202210.2147/OTT.S3530549005127González-MartínAHarterPLearyALorussoDMillerREPothuriBRay-CoquardITanDSPBelletEOakninANewly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upAnn Oncol34833848202310.1016/j.annonc.2023.07.01137597580QuaresimaBRomeoFFanielloMCDi SanzoMLiuCGLavecchiaATaccioliCGaudioEBaudiFTrapassoFBRCA1 5083del19 mutant allele selectively up-regulates periostin expression in vitro and in vivoClin Cancer Res1467976803200810.1158/1078-0432.CCR-07-520818980973CruglianoTQuaresimaBGaspariMFanielloMCRomeoFBaudiFCudaGCostanzoFVenutaSSpecific changes in the proteomic pattern produced by the BRCA1-Ser1841Asn missense mutationInt J Biochem Cell Biol39220226200710.1016/j.biocel.2006.08.005WeiXSunLSladeEFierhellerCTOxleySKalraASiaJSiderisMMcCluggageWGBromhamNCost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast CancerJAMA Netw Open7e2355324202410.1001/jamanetworkopen.2023.553243833499910858404HansonHKulkarniALoongLKavanaughGTorrBAllenSAhmedMAntoniouACCleaverRDabirTUK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2J Med Genet60417429202310.1136/jmg-2022-108898ScicchitanoSFanielloMCMesuracaMZinc Finger 521 Modulates the Nrf2-notch signaling pathway in human ovarian carcinomaInt J Mol Sci2414755202310.3390/ijms2419147553783420210572470ScicchitanoSMontalciniYLucchinoVMelocchiVGigantinoVChiarellaEBianchiFWeiszAMesuracaMEnhanced ZNF521 expression induces an aggressive phenotype in human ovarian carcinoma cell linesPLoS One17e0274785202210.1371/journal.pone.0274785361910069529122ChenYHeZYangSChenCXiongWHeYLiuSRUNX1 knockdown induced apoptosis and impaired EMT in high-grade serous ovarian cancer cellsJ Transl Med21886202310.1186/s12967-023-04762-83805781610702124ColletLHanvicBTurinettoMTreilleuxIChopinNLe SauxORay-CoquardIBRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: State of the art and forthcoming challengesFront Oncol141354427202410.3389/fonc.2024.13544273854483210965616WangLWangXZhuXZhongLJiangQWangYTangQLiQZhangCWangHZouDDrug resistance in ovarian cancer: From mechanism to clinical trialMol Cancer2366202410.1186/s12943-024-01967-33853916110976737MarjamaaAGibbsBKotrbaCMasamhaCPThe role and impact of alternative polyadenylation and miRNA regulation on the expression of the multidrug resistance-associated protein 1 (MRP-1/ABCC1) in epithelial ovarian cancerSci Rep1317476202310.1038/s41598-023-44548-y3783878810576765ElsnerovaKBartakovaATihlarikJBoudaJRobLSkapaPHrudaMGutIMohelnikova-DuchonovaBSoucekPVaclavikovaRGene expression profiling reveals novel candidate markers of ovarian carcinoma intraperitoneal metastasisJ Cancer835983606201710.7150/jca.20766291519465687176TengQXLeiZNWangJQYangYWuZXAcharekarNDZhangWYoganathanSPanYWurpelJOverexpression of ABCC1 and ABCG2 confers resistance to talazoparib a poly (ADP-Ribose) polymerase inhibitorDrug Resist Updat73101028202410.1016/j.drup.2023.101028SniegowskiTKoracKBhutiaYDGanapathyVSLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine-Glycine-One-Carbon Pathways in CancerPharmaceuticals14216202110.3390/ph14030216338066758000594ChiarellaEAloisioAScicchitanoSTodoertiKCosentinoEGLicoDNeriAAmodioNBondHMMesuracaMZNF521 Enhances MLL-AF9-Dependent hematopoietic stem cell transformation in acute myeloid leukemias by altering the gene expression landscapeInt J Mol Sci2210814202110.3390/ijms221910814346391548509509BharadwajRJaiswalSVelarde de la CruzEEThakareRPTargeting solute carrier transporters (SLCs) as a therapeutic target in different cancersDiseases1263202410.3390/diseases120300633853498710968914KairaKNakamuraKHirakawaTImaiHTominagaHOriuchiNNagamoriSKanaiYTsukamotoNOyamaTPrognostic significance of L-type amino acid transporter 1 (LAT1) expression in patients with ovarian tumorsAm J Transl Res7116111712015262797594532748GuoHXuYWangFShenZTuoXQianHWangHWangKClinical associations between ASCT2 and p-mTOR in the pathogenesis and prognosis of epithelial ovarian cancerOncol Rep4037253733201830272366HuangXLuoYLiXCirc_0072995 promotes ovarian cancer progression through regulating miR-122-5p/SLC1A5 AxisBiochem Genet60153172202210.1007/s10528-021-10092-5MaHQuSZhaiYYangXcirc_0025033 promotes ovarian cancer development via regulating the hsa_miR-370-3p/SLC1A5 axisCell Mol Biol Lett2794202210.1186/s11658-022-00364-2362731409588225VillagomezFRLangJRosarioFJNunez-AvellanedaDWebbPNevilleMWoodruffERBitlerBGClaudin-4 Modulates Autophagy via SLC1A5/LAT1 as a Mechanism to Regulate MicronucleiCancer Res Commun416251642202410.1158/2767-9764.CRC-24-02403886736011218812ZhangCShafaq-ZadahMPawlingJHeskethGGDransartEPacholczykKLongoJGingrasACPennLZJohannesLDennisJWSLC3A2 N-glycosylation and Golgi remodeling regulate SLC7A amino acid exchangers and stress mitigationJ Biol Chem299105416202310.1016/j.jbc.2023.1054163791880810698284MilkereitRPersaudAVanoaicaLGuetgAVerreyFRotinDLAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activationNat Commun67250201510.1038/ncomms8250259985674455107ParkEKimHYoonSJangBThe role of CD98 heavy chain in cancer developmentHistol Histopathol16187492024HeJLiuDLiuMTangRZhangDCharacterizing the role of SLC3A2 in the molecular landscape and immune microenvironment across human tumorsFront Mol Biosci9961410202210.3389/fmolb.2022.961410359922699388758CuiYQinLTianDWangTFanLZhangPWangZZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2Chemotherapy63262271201810.1159/00049386430481785ZhouXYLiJYTanJTHuangLiYLNieXCXiaPClinical significance of the CD98hc-CD147 complex in ovarian cancer: A bioinformatics analysisJ Obstet Gynaecol432188085202310.1080/01443615.2023.218808536930892QinLLiTLiuYHigh SLC4A11 expression is an independent predictor for poor overall survival in grade 3/4 serous ovarian cancerPLoS One12e0187385201710.1371/journal.pone.0187385290919605665559EstrellaVChenTLloydMWojtkowiakJCornnellHHIbrahim-HashimABaileyKBalagurunathanYRothbergJMSloaneBFAcidity generated by the tumor microenvironment drives local invasionCancer Res7315241535201310.1158/0008-5472.CAN-12-2796232885103594450GatenbyRAGawlinskiETGmitroAFKaylorBGilliesRJAcid-mediated tumor invasion: A multidisciplinary studyCancer Res6652165223200610.1158/0008-5472.CAN-05-419316707446SanhuezaCAraosJNaranjoLToledoFBeltránARRamírezMAGutiérrezJPardoFLeivaASobreviaLSodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancerBiochim Biophys Acta Mol Basis Dis18638191201710.1016/j.bbadis.2016.10.013GongWChenYZhangYPrognostic and clinical significance of Solute Carrier Family 7 Member 1 in ovarian cancerTransl Cancer Res10602612202110.21037/tcr-20-2744HushmandiKEinollahiBSaadatSHLeeEHCFaraniMROkinaEHuhYSNabaviNSalimimoghadamSKumarAPAmino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapyMol Metab84101952202410.1016/j.molmet.2024.1019523870551311112377YouSZhuXYangYDuXSongKZhengQZengPYaoQSLC7A1 overexpression is involved in energy metabolism reprogramming to induce tumor progression in epithelial ovarian cancer and is associated with immune-infiltrating cellsJ Oncol20225864826202210.1155/2022/5864826361317909484923SunTBiFLiuZYangQSLC7A2 serves as a potential biomarker and therapeutic target for ovarian cancerAging (Albany NY)121328113296202010.18632/aging.103433326470707377849JeckelmannJMZauggJMorozovaVMüllerJKantipudiSSchroederMGraffJAlbrechtCAltmannKHGertschJFotiadisDStructure, Function and Pharmacology of SLC7 Family Members and HomologuesChimia (Aarau)7610111018202210.2533/chimia.2022.1011JiangSZouJDongJShiHChenJLiYDuanXLiWLower SLC7A2 expression is associated with enhanced multidrug resistance, less immune infiltrates and worse prognosis of NSCLCCell Commun Signal219202310.1186/s12964-022-01023-x366397719838041WuXShenSQinJFeiWFanFGuJShenTZhangTChengXHigh co-expression of SLC7A11 and GPX4 as a predictor of platinum resistance and poor prognosis in patients with epithelial ovarian cancerBJOG129Suppl 2S40S49202210.1111/1471-0528.17327FantoneSPianiFOlivieriFRippoMRSiricoADi SimoneNMarzioniDTossettaGRole of SLC7A11/xCT in Ovarian CancerInt J Mol Sci25587202410.3390/ijms250105873820375810779187ZhangYDongKJiaXDuSWangDWangLQuHZhuSWangYWangZA novel extrachromosomal circular DNA related genes signature for overall survival prediction in patients with ovarian cancerBMC Med Genomics16140202310.1186/s12920-023-01576-x3733717010278296FanXRossDDArakawaHGanapathyVTamaiINakanishiTImpact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: A possible target for combination therapy with anti-proliferative aminopeptidase inhibitorsBiochem Pharmacol80811818201010.1016/j.bcp.2010.05.02120510678KajiMKabir-SalmaniMAnzaiNJinCJAkimotoYHoritaASakamotoAKanaiYSakuraiHIwashitaMProperties of L-type amino acid transporter 1 in epidermal ovarian cancerInt J Gynecol Cancer20329336201010.1111/IGC.0b013e3181d28e1320375792SatoKMiyamotoMTakanoMFuruyaKTsudaHSignificant relationship between the LAT1 expression pattern and chemoresistance in ovarian clear cell carcinomaVirchows Arch474701710201910.1007/s00428-019-02520-030637450BaczewskaMSupruniukEBojczukKGuzikPMilewskaPKonończukKDobrochJChabowskiAKnappPEnergy substrate transporters in high-grade ovarian cancer: Gene expression and clinical implicationsInt J Mol Sci238968202210.3390/ijms23168968360122309408757SekineMKohINakamotoKNosakaSTomonoKSugimotoJKudoYSelective inhibition of L-type amino acid transporter 1 suppresses cell proliferation in ovarian clear cell carcinomaAnticancer Res4325092517202310.21873/anticanres.1641837247931LiSYiZLiMZhuZBaicalein improves the chemoresistance of ovarian cancer through regulation of CirSLC7A6J Ovarian Res16212202310.1186/s13048-023-01285-03794098210631197WangXChenYWangXTianHWangYJinJShanZLiuYCaiZTongXStem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11Cancer Res8152175229202110.1158/0008-5472.CAN-21-0567343851818530936YangJZhouYXieSWangJLiZChenLMaoMChenCHuangAChenYMetformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancerJ Exp Clin Cancer Res40206202110.1186/s13046-021-02012-7341624238223374CaoNZhangFYinJZhangJBianXZhengGLiNLinYLuoLLPCAT2 inhibits colorectal cancer progression via the PRMT1/SLC7A11 axisOncogene4317141725202410.1038/s41388-024-02996-43860521411136653LeeJRohJLSLC7A11 as a gateway of metabolic perturbation and ferroptosis vulnerability in cancerAntioxidants (Basel)112444202210.3390/antiox11122444365526529774303ŠkubníkJSvobodová PavlíčkováVRumlTRimpelováSAutophagy in cancer resistance to paclitaxel: Development of combination strategiesBiomed Pharmacother161114458202310.1016/j.biopha.2023.11445836889112JyotsanaNTaKTDelGiornoKEThe Role of Cystine/Glutamate Antiporter SLC7A11/xCT in the Pathophysiology of CancerFront Oncol12858462202210.3389/fonc.2022.858462352807778904967YangJWangCChengSZhangYJinYZhangNWangYConstruction and validation of a novel ferroptosis-related signature for evaluating prognosis and immune microenvironment in ovarian cancerFront Genet131094474202310.3389/fgene.2022.1094474366858519849594CongYCaiGDingCZhangHChenJLuoSLiuJDisulfidptosis-related signature elucidates the prognostic, immunologic, and therapeutic characteristics in ovarian cancerFront Genet151378907202410.3389/fgene.2024.13789073869487511061395YinFYiSWeiLZhaoBLiJCaiXDongCLiuXMicroarray-based identification of genes associated with prognosis and drug resistance in ovarian cancerJ Cell Biochem12060576070201910.1002/jcb.27892KeYChenXSuYChenCLeiSXiaLWeiDZhangHDongCLiuXYinFLow Expression of SLC7A11 Confers Drug Resistance and Worse Survival in Ovarian Cancer via Inhibition of Cell Autophagy as a Competing Endogenous RNAFront Oncol11744940202110.3389/fonc.2021.744940347905728591223ZhangXZhengXYingXXieWYinYWangXCEBPG suppresses ferroptosis through transcriptional control of SLC7A11 in ovarian cancerJ Transl Med21334202310.1186/s12967-023-04136-03721057510199564OgiwaraHTakahashiKSasakiMKurodaTYoshidaHWatanabeRMaruyamaAMakinoshimaHChiwakiFSasakiHTargeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient CancersCancer Cell35177190.e8201910.1016/j.ccell.2018.12.00930686770HanYFuLKongYJiangCHuangLZhangHSTEAP3 Affects Ovarian Cancer Progression by Regulating Ferroptosis through the p53/SLC7A11 PathwayMediators Inflamm20244048527202410.1155/2024/40485273844035410911874JinYChenLLiLHuangGHuangHTangCSNAI2 promotes the development of ovarian cancer through regulating ferroptosisBioengineered1364516463202210.1080/21655979.2021.2024319352208728974033WangYWangSZhangWHRD1 functions as a tumor suppressor in ovarian cancer by facilitating ubiquitination-dependent SLC7A11 degradationCell Cycle2211161126202310.1080/15384101.2023.21781023680991710081055ChiarellaEAloisioAScicchitanoSBondHMMesuracaMRegulatory Role of microRNAs Targeting the Transcription Co-Factor ZNF521 in Normal Tissues and CancersInt J Mol Sci228461202110.3390/ijms22168461344451648395128CaiLHuXYeLBaiPJieYShuKLong non-coding RNA ADAMTS9-AS1 attenuates ferroptosis by Targeting microRNA-587/solute carrier family 7 member 11 axis in epithelial ovarian cancerBioengineered1382268239202210.1080/21655979.2022.2049470353114579161843SunBZhangLWuBLuoXA Morpholine Derivative N-(4-Morpholinomethylene) ethanesulfonamide induces ferroptosis in tumor cells by targeting NRF2Biol Pharm Bull47417426202410.1248/bpb.b23-0054438296488ShenXPengYZhouHYeXHanZShiXA Pt(II) complex bearing N-heterocycle ring induced ferroptotic cell death in ovarian cancerJ Inorg Biochem253112502202410.1016/j.jinorgbio.2024.11250238335582ZhangWLiuTJiangLChenJLiQWangJImmunogenic cell death-related gene landscape predicts the overall survival and immune infiltration status of ovarian cancerFront Genet131001239202210.3389/fgene.2022.1001239364250719679378SzadvariIHudecovaSChovancovaBMatuskovaMCholujovaDLencesovaLValerianDOndriasKBabulaPKrizanovaOSodium/calcium exchanger is involved in apoptosis induced by H2S in tumor cells through decreased levels of intracellular pHNitric Oxide8719201910.1016/j.niox.2019.02.01130849492WangHLongXWangDLouMZouDChenRNianWZhouQIncreased expression of Na+/H+ exchanger isoform 1 predicts tumor aggressiveness and unfavorable prognosis in epithelial ovarian cancerOncol Lett16671367202018304058136202499YuanSHeSHLiLYXiSWengHZhangJHWangDQGuoMMZhangHWangSYA potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1Cell Death Dis147202310.1038/s41419-022-05544-89822915LiuJYDaiYBLiXCaoKXieDTongZTLongZXiaoHChenMKYeYLSolute carrier family 12 member 5 promotes tumor invasion/metastasis of bladder urothelial carcinoma by enhancing NF-κB/MMP-7 signaling pathwayCell Death Dis Mar8e2691201710.1038/cddis.2017.118TongQQinWLiZHLiuCWangZCChuYXuXDSLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changesCancer Med1285268541202310.1002/cam4.56053664517110134347XuLLiXCaiMChenJLiXWuWKKangWTongJToKFGuanXYIncreased expression of Solute carrier family 12 member 5 via gene amplification contributes to tumour progression and metastasis and associates with poor survival in colorectal cancerGut65635646201610.1136/gutjnl-2014-308257JiangYLiaoHLChenLYA Pan-Cancer Analysis of SLC12A5 Reveals Its Correlations with Tumor ImmunityDis Markers20213062606202110.1155/2021/3062606346307368495467YangGPHeWPTanJFYangZXFanRRMaNFWangFWChenLLiYShenHWOverexpression of SLC12A5 is associated with tumor progression and poor survival in ovarian carcinomaInt J Gynecol Cancer2912801284201910.1136/ijgc-2019-00022931570543FiselPSchaeffelerESchwabMClinical and functional relevance of the Monocarboxylate transporter family in disease pathophysiology and drug therapyClin Transl Sci11352364201810.1111/cts.12551296607776039204HanahanDHallmarks of Cancer: New DimensionsCancer Discov123146202210.1158/2159-8290.CD-21-105935022204NavarroCOrtegaÁSantelizRGarridoBChacínMGalbanNVeraIDe SanctisJBBermúdezVMetabolic Reprogramming in Cancer Cells: Emerging molecular mechanisms and novel therapeutic approachespharmaceutics141303202210.3390/pharmaceutics14061303357458759227908LatifAChadwickALKitsonSJGregsonHJSivalingamVNBoltonJMcVeyRJRobertsSAMarshallKMWilliamsKJMonocarboxylate transporter 1 (MCT1) is an independent prognostic biomarker in endometrial cancerBMC Clin Pathol1727201710.1186/s12907-017-0067-7SohrabiEMoslemiMRezaieENafissiNKhalediMAfkhamiHFathiJZekriAThe tissue expression of MCT3, MCT8, and MCT9 genes in women with breast cancerGenes Genomics4310651077202110.1007/s13258-021-01116-w34097251ChatterjeePBhowmikDRoySSA systemic analysis of monocarboxylate transporters in ovarian cancer and possible therapeutic interventionsChannels (Austin)172273008202310.1080/19336950.2023.22730083793472110631444ChengLLuWKulkarniBPejovicTYanXChiangJHHoodLOdunsiKLinBAnalysis of chemotherapy response programs in ovarian cancers by the next-generation sequencing technologiesGynecol Oncol11159169201010.1016/j.ygyno.2010.01.041JanuchowskiRZawieruchaPRucińskiMAndrzejewskaMWojtowiczKNowickiMZabelMDrug transporter expression profiling in chemoresistant variants of the A2780 ovarian cancer cell lineBiomed Pharmacother68447453201410.1016/j.biopha.2014.02.00224814220LeeJPeñaMMNoseYThieleDJBiochemical characterization of the human copper transporter Ctr1J Biol Chem27743804387200210.1074/jbc.M104728200PurisEFrickerGGyntherMThe role of solute carrier transporters in efficient anticancer drug delivery and therapyPharmaceutics15364202310.3390/pharmaceutics15020364368396869966068WuGPengHTangMYangMWangJHuYLiZLiJLiZSongLZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expressionEBioMedicine71103558202110.1016/j.ebiom.2021.103558345210548441092BanerjeeSDrapkinRRichardsonDLBirrerMTargeting NaPi2b in ovarian cancerCancer Treat Rev112102489202310.1016/j.ctrv.2022.102489BondesonDPPaolellaBRAsfawARothbergMVSkipperTALanganCMesaGGonzalezASurfaceLEItoKPhosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancerNat Cancer3681695202210.1038/s43018-022-00360-7354373179246846VlasenkovaRNurgalievaAAkberovaNBogdanovMKiyamovaRCharacterization of SLC34A2 as a potential prognostic marker of oncological diseasesBiomolecules111878202110.3390/biom11121878349445228699446StilesLIFerraoKMehtaKJRole of zinc in health and diseaseClin Exp Med2438202410.1007/s10238-024-01302-63836703510874324ChenBYuPChanWNXieFZhangYLiangLLeungKTLoKWYuJTseGMKCellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targetsSignal Transduct Target Ther96202410.1038/s41392-023-01679-y3816946110761908Vogel-GonzálezMMusa-AfanehDRivera GilPVicenteRZinc Favors Triple-negative breast cancer's microenvironment modulation and cell plasticityInt J Mol Sci229188202110.3390/ijms22179188345020918431059LiuMYangJZhangYZhouZCuiXZhangLFungKMZhengWAllardFDYeeEUZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional MechanismClin Cancer Res2431863196201810.1158/1078-0432.CCR-18-0263296154567006048FanQZhangWEmersonREXuYZIP4 is a novel cancer stem cell marker in high-grade serous ovarian cancerCancers (Basel)123692202010.3390/cancers12123692333169867764492ScheiterAEvertKReibenspiesLCiglianoAAnnweilerKMüllerKPöhmererLMXuHCuiGItzelTRASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: New therapeutic venuesMol Oncol1610911118202210.1002/1878-0261.13135FanQCaiQLiPWangWWangJGerryEWangTLShihIMNephewKPXuYThe novel ZIP4 regulation and its role in ovarian cancerOncotarget89009090107201710.18632/oncotarget.21435291638135685734CaiQFanQBuechleinAMillerDNephewKPLiuSWanJXuYChanges in mRNA/protein expression and signaling pathways in in vivo passaged mouse ovarian cancer cellsPLoS One13e0197404201810.1371/journal.pone.0197404299279336013233ChengXWangJLiuCJiangTYangNLiuDZhaoHXuZZinc transporter SLC39A13/ZIP13 facilitates the metastasis of human ovarian cancer cells via activating Src/FAK signaling pathwayJ Exp Clin Cancer Res40199202110.1186/s13046-021-01999-3341546188215834Akasu-NagayoshiYHayashiTKawabataAShimizuNYamadaAYokotaNNakatoRShirahigeKOkamotoAAkiyamaTPHOSPHATE exporter XPR1/SLC53A1 is required for the tumorigenicity of epithelial ovarian cancerCancer Sci11320342043202210.1111/cas.15358353775289207365ChandraAPiusCNabeelMNairMVishwanathaJKAhmadSBashaROvarian cancer: Current status and strategies for improving therapeutic outcomesCancer Med870187031201910.1002/cam4.2560315608286853829SatoSShojiTJoAOtsukaHAbeMTatsukiSChibaYTakatoriEKaidoYNagasawaTAntibody-Drug Conjugates: The new treatment approaches for ovarian cancerCancers (Basel)162545202410.3390/cancers161425453906118411275051KarpelHCPowellSSPothuriBAntibody-Drug Conjugates in Gynecologic CancerAm Soc Clin Oncol Educ Book43e390772202310.1200/EDBK_39077237229642
Schematic representation of SLCs responsible for transporting various substances across the cell membrane in OC. The figure illustrates examples of SLCs demonstrating the transporter types and their specific localization in OC. Uniporters: SLC53A1 (efflux); SLC7A1, SLC7A2, SLC31A1, SLC39A4, SLC32A2/SLC7A5 and SLC39A13 (influx). Antiporters: SLC3A2, SLC4A11, SLC7A and SLC9A1. Symporters: SLC1A5, SLC12A5, SLC16A3 and SLC34A2. The xCT system involving SLC7A11 in the exchange of L-Cystine/L-Glu across the plasma membrane. EAAs, essential amino acids; LAPTM4b, lysosome associated protein transmembrane 4B; SLC, solute carrier. Created with BioRender software.
Transport type and location of SLCs in ovarian cancer.