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Glutamine supports biosynthesis and redox homeostasis in cancer cells. The glutamine transporter ASCT2 is highly expressed in prostate cancer and is associated with higher Gleason grade. Although ASCT2 inhibition induces reactive oxygen species (ROS) accumulation and apoptosis, cancer cells may activate antioxidant adaptive mechanisms that limit therapeutic efficacy. Here, we identified an NRF2/xCT‐dependent redox‐adaptive response following ASCT2 inhibition in prostate cancer. Mechanistically, ASCT2 inhibition induced ROS accumulation, promoted nuclear translocation of NRF2, and upregulated xCT together with other NRF2‐associated antioxidant genes. Functional redox analysis showed that ASCT2 inhibition reduced glutathione‐dependent redox capacity, whereas combined ASCT2 and xCT inhibition further increased GSSG accumulation and markedly decreased GSH levels and the GSH/GSSG ratio. These fin were further validated in C4‐2 cells as an additional prostate cancer model. Cell death discrimination assays showed that combined ASCT2 and xCT inhibition induced lipid peroxidation that was partially rescued by ferrostatin‐1, whereas z‐VAD produced a stronger rescue effect and Annexin V/PI staining confirmed prominent apoptotic cell death. In castrated 22Rv1 xenograft models, combined treatment with V‐9302 and erastin produced the strongest inhibition of tumor growth without significant body weight loss during treatment. Collectively, these findings demonstrate that NRF2/xCT‐mediated residual glutathione redox buffering functions as an adaptive survival mechanism following ASCT2 inhibition and provide a mechanistic rationale for combined targeting of ASCT2 and xCT to overcome redox‐adaptive resistance in prostate cancer.

The purpose of the present study was to evaluate the anti‐cancer property of Lobetyolin on colorectal cancer and explore its potential mechanism. Lobetyolin was incubated with HCT‐116 cells in the absence or presence of ASCT2 inhibitor Benser or p53 inhibitor Pifithrin‐α. The levels of glutamine, glutamic acid, α‐ketoglutarate, ATP and GSH were determined to measure the glutamine metabolism. Annexin V‐FITC/PI staining and TUNEL assay were applied to estimate the apoptotic condition. The levels of ASCT2 were examined by RT‐qPCR, Western blot and immunofluorescence staining. The expressions of cleaved‐caspase‐3, caspase‐3, cleaved‐caspase‐7, caspase‐7, cleaved‐PARP, PARP, p53, p21, bax and survivin were detected using Western blot analysis. As a result, the treatment with Lobetyolin effectively induced apoptosis and glutamine metabolism in HCT‐116 cells through ASCT2 signalling. The inhibition of ASCT2 reduced the glutamine‐related biomarkers and augmented the apoptotic process. We further found that the effect of Lobetyolin on HCT‐116 was related to the expressions of p21 and bax, and transportation of p53 to nucleus. The inhibition of p53 by Pifithrin‐α promoted the inhibitory effect of Lobetyolin on ASCT2‐mediated apoptosis. Lobetyolin also exerted anti‐cancer property in nude mice. In conclusion, the present work suggested that Lobetyolin could induce the apoptosis via the inhibition of ASCT2‐mediated glutamine metabolism, which was possibly governed by p53.

Cancer cells are metabolically reprogrammed to support their high rates of proliferation, continuous growth, survival, invasion, metastasis, and resistance to cancer treatments. Among changes in cancer cell bioenergetics, the role of glutamine metabolism has been receiving increasing attention. Increased glutaminolysis in cancer cells is associated with increased expression of membrane transporters that mediate the cellular uptake of glutamine. ASCT2 (Alanine, Serine, Cysteine Transporter 2) is a Na+-dependent transmembrane transporter overexpressed in cancer cells and considered to be the primary transporter for glutamine in these cells. The possibility of inhibiting ASCT2 for antineoplastic therapy is currently under investigation. In this article, we will present the pharmacological agents currently known to act on ASCT2, which have been attracting attention in antineoplastic therapy research. We will also address the impact of ASCT2 inhibition on the prognosis of some cancers. We conclude that ASCT2 inhibition and combination of ASCT2 inhibitors with other anti-tumor therapies may be a promising antineoplastic strategy. However, more research is needed in this area.

SLC1A5, known as ASCT2, is a neutral amino acid transporter belonging to the SLC1 family and localized in the plasma membrane of several body districts. ASCT2 is an acronym standing for Alanine, Serine, Cysteine Transporter 2 even if the preferred substrate is the conditionally essential amino acid glutamine, with cysteine being a modulator and not a substrate. The studies around amino acid transport in cells and tissues began in the '60s by using radiolabeled compounds and competition assays. After identification of murine and human genes, the function of the coded protein has been studied in cell system and in proteoliposomes revealing that this transporter is a Na dependent antiporter of neutral amino acids, some of which are only inwardly transported and others are bi-directionally exchanged. The functional asymmetry merged with the kinetic asymmetry in line with the physiological role of amino acid pool harmonization. An intriguing function has been described for ASCT2 that is exploited as a receptor by a group of retroviruses to infect human cells. Interactions with scaffold proteins and post-translational modifications regulate ASCT2 stability, trafficking and transport activity. Two asparagine residues, namely N163 and N212, are the sites of glycosylation that is responsible for the definitive localization into the plasma membrane. ASCT2 expression increases in highly proliferative cells such as inflammatory and stem cells to fulfill the augmented glutamine demand. Interestingly, for the same reason, the expression of ASCT2 is greatly enhanced in many human cancers. This finding has generated interest in its candidacy as a pharmacological target for new anticancer drugs. The recently solved 3D structure of ASCT2 will aid in the rational design of such therapeutic compounds.

Amino acids are indispensable for the growth of cancer cells. This includes essential amino acids, the carbon skeleton of which cannot be synthesized, and conditionally essential amino acids, for which the metabolic demands exceed the capacity to synthesize them. Moreover, amino acids are important signaling molecules regulating metabolic pathways, protein translation, autophagy, defense against reactive oxygen species, and many other functions. Blocking uptake of amino acids into cancer cells is therefore a viable strategy to reduce growth. A number of studies have used genome-wide silencing or knock-out approaches, which cover all known amino acid transporters in a large variety of cancer cell lines. In this review, these studies are interrogated together with other databases to identify vulnerabilities with regard to amino acid transport. Several themes emerge, such as synthetic lethality, reduced redundancy, and selective vulnerability, which can be exploited to stop cancer cell growth.

Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.

Oncogenic KRAS mutations develop unique metabolic dependencies on nutrients to support tumor metabolism and cell proliferation. In particular, KRAS mutant cancer cells exploit amino acids (AAs) such as glutamine and leucine, to accelerate energy metabolism, redox balance through glutathione synthesis and macromolecule biosynthesis. However, the identities of the amino acid transporters (AATs) that are prominently upregulated in KRAS mutant cancer cells, and the mechanism regulating their expression have not yet been systematically investigated. Here, we report that the majority of the KRAS mutant colorectal cancer (CRC) cells upregulate selected AATs (SLC7A5/LAT1, SLC38A2/SNAT2, and SLC1A5/ASCT2), which correlates with enhanced uptake of AAs such as glutamine and leucine. Consistently, knockdown of oncogenic KRAS downregulated the expression of AATs, thereby decreasing the levels of amino acids taken up by CRC cells. Moreover, overexpression of mutant KRAS upregulated the expression of AATs (SLC7A5/LAT1, SLC38A2/SNAT2, and SLC1A5/ASCT2) in KRAS wild‐type CRC cells and mouse embryonic fibroblasts. In addition, we show that the YAP1 (Yes‐associated protein 1) transcriptional coactivator accounts for increased expression of AATs and mTOR activation in KRAS mutant CRC cells. Specific knockdown of AATs by shRNAs or pharmacological blockage of AATs effectively inhibited AA uptake, mTOR activation, and cell proliferation. Collectively, we conclude that oncogenic KRAS mutations enhance the expression of AATs via the hippo effector YAP1, leading to mTOR activation and CRC cell proliferation. Here, we demonstrate that oncogenic KRAS mutations upregulate the expression of selected amino acid transporters in colorectal cancer (CRC) cells through the hippo signaling effector YAP1. Upregulation of SLC1A5/ASCT2 and SLC38A2/SNAT2 led to intracellular l‐glutamine accumulation. l‐glutamine was reciprocally exported via SLC7A5/LAT1 in exchange for l‐leucine, a key activator of mTORC1. Intracellular l‐leucine led to the activation of mTORC1, thereby promoting KRAS mutant CRC cell proliferation.

System ASC amino acid transporter-2 (ASCT2) is abnormally highly expressed in tumor cells and closely associated with a poor prognosis, but the regulatory mechanism of abnormally high ASCT2 expression is scarcely investigated. MicroRNAs (miRNAs) that are abnormally expressed regulate gene expression to have either oncogenic or tumor-suppressive effects in pancreatic cancer (PC). MicroRNA-122-5p (miR-122-5p) dysregulation has been seen in various cancer entities, but the biological function of miR-122-5p in PC and its regulation mechanisms remain unknown. Western blot and quantitative RT-PCR were used to measure the expression of miR-122-5p, ASCT2, and apoptosis-related proteins. CCK-8 assays were used to elucidate the effect on cell proliferation. Flow cytometry (FCM) assays were utilized to evaluate cell apoptosis. A dual-luciferase reporter assay was utilized to determine if miR-122a-5p directly targeted ASCT2. Glutamine consumption and the α-ketoglutarate (α-KG) and adenosine triphosphate (ATP) contents were determined using respective assays. MiR-122-5p expression was low whereas ASCT2 expression was high in PC tissues and cells. Overexpressing miR-122-5p restrained pancreatic cancer cell proliferation, accelerated apoptosis, and decreased glutamine consumption, α-ketoglutarate (α-KG) production and ATP generation, whereas suppressing miR-122-5p had the opposite effect. Moreover, the reporter gene test established ASCT2 as a miR-122-5p target. Overexpression of miR-122-5p decreased ASCT2 expression, whereas miR-122-5p repression increased ASCT2 expression. In addition, miR-122-5p also regulated apoptosis-related pathways. MiR-122-5p may function as a tumor suppressor by inhibiting the proliferation, glutamine metabolism, and inducing apoptosis via altering the expression of ASCT2 in pancreatic cancer cells.

Amino acid transporters are abundant amongst the solute carrier family and have an important role in facilitating the transfer of amino acids across cell membranes. Because of their impact on cell nutrient distribution, they also appear to have an important role in the growth and development of cancer. Naturally, this has made amino acid transporters a novel target of interest for the development of new anticancer drugs. Many attempts have been made to develop inhibitors of amino acid transporters to slow down cancer cell growth, and some have even reached clinical trials. The purpose of this review is to help organize the available information on the efforts to discover amino acid transporter inhibitors by focusing on the amino acid transporters ASCT2 (SLC1A5), LAT1 (SLC7A5), xCT (SLC7A11), SNAT1 (SLC38A1), SNAT2 (SLC38A2), and PAT1 (SLC36A1). We discuss the function of the transporters, their implication in cancer, their known inhibitors, issues regarding selective inhibitors, and the efforts and strategies of discovering inhibitors. The goal is to encourage researchers to continue the search and development within the field of cancer treatment research targeting amino acid transporters.

Targeting the function of membrane transporters in cancer stemlike cells is a potential new therapeutic approach. Cystine‐glutamate antiporter xCT expressed in CD44 variant (CD44v)‐expressing cancer cells contributes to the resistance to oxidative stress as well as cancer therapy through promoting glutathione (GSH)‐mediated antioxidant defense. Amino acid transport by xCT might, thus, be a promising target for cancer treatment, whereas the determination factors for cancer cell sensitivity to xCT‐targeted therapy remain unclear. Here, we demonstrate that high expression of xCT and glutamine transporter ASCT2 is correlated with undifferentiated status and diminished along with cell differentiation in head and neck squamous cell carcinoma (HNSCC). The cytotoxicity of the xCT inhibitor sulfasalazine relies on ASCT2‐dependent glutamine uptake and glutamate dehydrogenase (GLUD)‐mediated α‐ketoglutarate (α‐KG) production. Metabolome analysis revealed that sulfasalazine treatment triggers the increase of glutamate‐derived tricarboxylic acid cycle intermediate α‐KG, in addition to the decrease of cysteine and GSH content. Furthermore, ablation of GLUD markedly reduced the sulfasalazine cytotoxicity in CD44v‐expressing stemlike HNSCC cells. Thus, xCT inhibition by sulfasalazine leads to the impairment of GSH synthesis and enhancement of mitochondrial metabolism, leading to reactive oxygen species (ROS) generation and, thereby, triggers oxidative damage. Our findings establish a rationale for the use of glutamine metabolism (glutaminolysis)‐related genes, including ASCT2 and GLUD, as biomarkers to predict the efficacy of xCT‐targeted therapy for heterogeneous HNSCC tumors. Competition exists between xCT‐mediated cystine uptake and GLUD‐mediated alpha‐KG generation.