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δT inhibits glutamine transporters (LAT-1 and ASCT2) and the mTOR pathway in A549 and H1299 cells. (A) The expressions of LAT-1, ASCT2, p-mTOR, mTOR, p-4EBP-1, 4EBP1, and β-actin proteins were detected by Western blot analysis in A549 and H1299 after treating with 0 µM and 30 µM concentrations of δT for 72 h. (B) The fate of glutamine uptake in A549 and H1299 involving metabolites (purple), associated key proteins (pink), and functions (orange). Glutamine in cancer facilitates exchanging of EAAs (essential amino acids) into proliferating cells via glutamine transporters (LAT1 and ASCT2), which induces mTOR activation in A549 and H1299. Activated mTOR then promotes protein translation and cell growth via activation of its downstream genes 4EBP1. The black arrows indicate pathway direction, while the red downward arrows indicate inhibition.

δT inhibits glutamine transporters (LAT-1 and ASCT2) and the mTOR pathway in A549 and H1299 cells. (A) The expressions of LAT-1, ASCT2, p-mTOR, mTOR, p-4EBP-1, 4EBP1, and β-actin proteins were detected by Western blot analysis in A549 and H1299 after treating with 0 µM and 30 µM concentrations of δT for 72 h. (B) The fate of glutamine uptake in A549 and H1299 involving metabolites (purple), associated key proteins (pink), and functions (orange). Glutamine in cancer facilitates exchanging of EAAs (essential amino acids) into proliferating cells via glutamine transporters (LAT1 and ASCT2), which induces mTOR activation in A549 and H1299. Activated mTOR then promotes protein translation and cell growth via activation of its downstream genes 4EBP1. The black arrows indicate pathway direction, while the red downward arrows indicate inhibition.

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The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, and protein synthesis. Seen as novel concepts in cancer development...

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Context 1
... Western blot analysis was performed to investigate the effect of δT on the mTOR pathway and glutamine transporters. Upon intervention with δT (30 µM), the glutamine transporters (LAT-1 and ASCT2) and key mTOR pathway proteins (P-mTOR and p-4EBP-1) were found to be inhibited, relative to the untreated controls (Figure 4). Metabolites ...
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... Western blot analysis was performed to investigate the effect of δT on the mTOR pathway and glutamine transporters. Upon intervention with δT (30 µM), the glutamine transporters (LAT-1 and ASCT2) and key mTOR pathway proteins (P-mTOR and p-4EBP-1) were found to be inhibited, relative to the untreated controls (Figure 4). The fate of glutamine uptake in A549 and H1299 involving metabolites (purple), associated key proteins (pink), and functions (orange). ...
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... facilitates glutamine efflux in exchange for the influx of leucine and other essential amino acids (EAA) across the cell membrane; similarly, ASCT2 mediates uptake of neutral amino acids including glutamine [51]. Our observations from western blot analysis established that δT treatments inhibit the expression of LAT-1 and ASCT2 (Figure 4). We also quantified detectable EAA including leucine in cell lysates, the concentration of which were decreased significantly after treating NSCLC cells with δT by NMR analysis. ...
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... if the inhibition of glutamine transporters and EAA uptake with δT treatment is valid, it is logical to expect inhibition or lower activation of mTOR pathway after treating with δT in NSCLC. Indeed, we observed lower activation of mTOR along with LAT-1 and ASCT2 after treating with δT, using Western blot analysis, which illustrates that inhibition of glutamine transporters affect the mTOR signaling pathway (Figure 4). mTOR functions are mediated by two downstream proteins, the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and p70 ribosomal S6 kinase 1 (p70S6K1, S6K1) (Figure 4) [55]. ...
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... we observed lower activation of mTOR along with LAT-1 and ASCT2 after treating with δT, using Western blot analysis, which illustrates that inhibition of glutamine transporters affect the mTOR signaling pathway (Figure 4). mTOR functions are mediated by two downstream proteins, the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and p70 ribosomal S6 kinase 1 (p70S6K1, S6K1) (Figure 4) [55]. ...
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... further confirmation, we tested the expression levels of downstream genes of mTOR namely P-4E-BP1. We observed the similar inhibitory effect on mTOR downstream proteins 4E-BP1suggesting an inhibitory effect of glutamine transporters passing through mTOR to downstream pathway (Figure 4). mTOR downstream proteins 4E-BP1 and S6K1 regulate F-actin reorganization, focal adhesion formation, and tissue remodeling through the proteolytic digestion of extracellular matrix via upregulation of matrix metalloproteinase 9 (MMP-9) [56]. ...
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... closer look into the intracellular metabolome of NSCLC cells revealed significant and potentially beneficial alterations in glutamine concentrations and related metabolism upon treatment with δT. The data purports that δT exerts its action by inhibiting glutamine uptake into proliferating cells by inhibition of glutamine transporters, thereby resulting in inhibition of cell proliferation and induction of apoptosis via downregulation of the mTOR pathway ( Figures 4B and 5). Through this work, NMR-based cellular metabolomics helps provide possible opportunities for evaluating the therapeutic effect of phytochemicals and systemic changes in cancer metabolism. ...

Citations

... Cysteine uptake is mediated by specific transporters, and cysteine can enter the cell as a free amino acid or as a dimer, cystine (107)(108)(109)(110)(111). The increased expression of xCT is described in cancer as being associated with more aggressive and chemoresistant phenotypes (100, 107,[112][113][114][115][116], and despite that most of these studies concern glutamate export, the role of cysteine uptake in the maintenance of those tumors can be assumed since for glutamate to leave the cell, cyst(e)ine entrance is mandatory. Although cystine is the main form taken up by cancer cells, cancer cells can also import cysteine directly (117) by overexpressing specific cysteine transporters, namely, the amino acid transporter 3 (EAAT3; SLC1A1 gene) (Nikolaos Pissimissis, Efstathia Papageorgiou, Peter Lembessis, Athanasios Armakolas, 2009; 108, 118) and the alanine-serine-cysteinetransporter 2 (ASCT2; SLC1A5 gene) (119)(120)(121). Since these transporters also mediate the transfer of other amino acids, their expression in the cancer context is not always associated with cysteine dependence. ...
Article
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Tumor metabolism is mandatory for the proper adaptation of malignant cells to the microenvironment and the acquisition of crucial cellular skills supporting the systemic spread of cancer. Throughout this journey, the contribution of the gut microbiota to the bioavailability of nutrients supporting the bioenergetic and biosynthetic requirements of malignant cells is an issue. This review will focus on the role of cysteine as a coin that mediates the metabolic crosstalk between microbiota and cancer. The key points enclose the way cysteine can be made available by the microbiota, by degradation of more complex compounds or by de novo synthesis, in order to contribute to the enrichment of the colonic microenvironment as well to the increase of cysteine systemic bioavailability. In addition, the main metabolic pathways in cancer that rely on cysteine as a source of energy and biomass will be pointed out and how the interspecific relationship with the microbiota and its dynamics related to aging may be relevant points to explore, contributing to a better understanding of cancer biology.
... It's verified that pharmacological blockade with V-9302 could result in attenuated cancer cell growth and proliferation, increased cell death and oxidative stress in lung cancer cell (22). Delta-tocotrienol (dT) treatment could similarly suppress the activity of SLC1A5 by derivatizing glutamate and glutathione, as well as some essential amino acids; while knockdown of circ-LDLRAD3 reduced the expression of SLC1A5 by sponging miR-137, which was eventually also observed to inhibit the development of NSCLC (23,24). SLC38A3, another transporter of Gln, activates the PDK1/AKT signaling pathway and promotes the metastasis of NSCLC by regulating the transport of Gln and histidine, indicating that SLC38A3 owns consistent therapeutic potential for the treatment of NSCLC (43). ...
Article
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Cancer cells tend to obtain the substances needed for their development depending on altering metabolic characteristics. Among the reorganized metabolic pathways, Glutamine pathway, reprogrammed to be involved in the physiological process including energy supply, biosynthesis and redox homeostasis, occupies an irreplaceable role in tumor cells and has become a hot topic in recent years. Lung cancer currently maintains a high morbidity and mortality rate among all types of tumors and has been a health challenge that researchers have longed to overcome. Therefore, this study aimed to clarify the essential role of glutamine pathway played in the metabolism of lung cancer and its potential therapeutic value in the interventions of lung cancer.
... Tocotrienols had also been claimed to induce apoptosis in human pulmonary adenocarcinoma that contained Ras mutation [93]. Additionally, a recent study showed that delta-tocotrienol inhibited glutamine uptake in non-small-cell lung cancer (NSCLC) cell lines A549 and H1229, which subsequently triggered the inhibition of cellular proliferation and induction of apoptosis via downregulation of the mTOR pathway [130]. ...
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Cancer remains a worrying cause of fatality worldwide despite the advancement in medicine. Among the dietary phytonutrients, tocotrienols have been extensively studied for their bioactivity against cancer. Palm oil is a rich source of tocotrienols. The most common formulation of tocotrienols is the tocotrienol-rich fraction of palm oil (TRF). The anticancer activities of tocotrienols were once presumed due to their antioxidant and free radical scavenging properties. However, recent evidence suggested that tocotrienols are capable of demonstrating cancer-fighting properties through their influence in various signalling pathways. The selectivity of tocot-rienols in killing cancer cells without affecting normal cells is indicative of their potential role in cancer treatment and prevention. Tocotrienols had proven to be particularly effective in the chemoprevention and treatment of breast, colorectal, pancreatic, prostate and liver cancers in many in vitro and in vivo animal experiments. However, the efficacy of tocotrienols in the management of human cancers are still questionable due to their poor bioavailability and lack of well-designed clinical trials. Nevertheless, due to their superb safety profiles, palm oil tocotrienols are still considered ideal candidates for future large scale clinical trials to prove their efficacy to treat or prevent cancers in humans.
... [8]. GPNA inhibits several transporters related to glutamine metabolism, such as ASCT2, LAT1, SNAT1, and SNAT [79,80]; V-9302 does not act by inhibiting ASCT2, but rather SNAT2, another glutamine transporter [81]; monoclonal antibodies recognizing ASCT2 appear to have a therapeutic role in cancer, slowing tumor growth and proliferation [9,13]; δ-tocotrienol inhibits not only ASCT2, but also LAT1 and the mTOR pathway [63]; miRNA-137 acts on ASCT2 mRNA, promoting its degradation and inhibiting its translation [69,70] Others In addition to these strategies, some drugs already known for other functions also seem to interfere with ASCT2-mediated glutamine transport. These include (a) topotecan, an inhibitor of DNA topoisomerase I (Topo I) which prevents both the replication of DNA and RNA synthesis, causing the death of malignant cells. ...
... It is used to treat non-small cell lung cancer and ovarian cancer [64]. Despite its anti-tumor effect acting as a Topo I inhibitor, according to a study that evaluated the impact of this compound on gastric cancer cell metabolism, topotecan also downregulates ASCT2, reducing the entry of glutamine into the cell, decreasing proliferation and increasing oxidative stress and apoptosis in a gastric cancer cell line in vitro [64]; (b) resveratrol, which downregulates ASCT2 in human hepatocellular carcinoma cell lines [10]; and (c) δ-tocotrienol, which inhibits not only ASCT2, but also LAT1 and the mTOR pathway in non-small cell lung cancer cell lines [63] (Fig. 2). ...
... So, ASCT2-based therapies may be also interesting for this type of cancer. In support of this, δ-tocotrienol was recently found to inhibit the glutamine transporters ASCT2 and LAT1, which prevents glutamine uptake into cancer cells, inhibiting the in vitro proliferation of malignant cells and increasing apoptosis, associated with mTOR pathway downregulation (Table 1) [63]. ...
Article
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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.
... The mTOR pathway is well described as deregulated in CRC, and the availability of AA functions as a regulator of this pathway, since a high AA microenvironmental bioavailability induces mTOR activity and consequent biological processes, such as protein translation [36]. Some studies report a relationship between LAT1 and ASCT2, with a two-step mechanism of these AAT being able to regulate mTOR pathway [37][38][39]. Firstly, ASCT2 regulates the intracellular concentration of glutamine, and in turn LAT1 uses this intracellular glutamine as an efflux substrate, in order to regulate the uptake of extracellular leucine, which will lead to an activation of mTOR signaling and consequent induction of cell growth and proliferation [40,41] (Figure 1). ...
... Firstly, ASCT2 regulates the intracellular concentration of glutamine, and in turn LAT1 uses this intracellular glutamine as an efflux substrate, in order to regulate the uptake of extracellular leucine, which will lead to an activation of mTOR signaling and consequent induction of cell growth and proliferation [40,41] (Figure 1). Furthermore, according to Rajasinghe and coworkers, the inhibition of glutamine uptake in proliferating cells, through the inhibition of glutamine transporters LAT1 and ASCT2, results in the inhibition of cell proliferation and induces apoptosis, through the downregulation of the mTOR pathway [38]. Thus, the inhibition of LAT1 and ASCT2 expression levels could represent a promising therapeutic approach for CRC since it would reduce the AA intake, consequently causing mTOR pathway inhibition and compromising cancer cell proliferation. ...
... The use of pharmacologic approaches against LAT1 and ASCT2 in cancers with overexpression of these two AA transporters seems be a promising strategy. In fact, over the last few years there was investment in the development of drugs against LAT1 and ASCT2 [26,38,42,43]. The design of drugs against these two AA transporters usually follows an approach based on substrate analogues, which act as competitive inhibitors [26]. ...
Article
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The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.
... In this section, we will explore the association between ASCT2 and LAT1 and these distinctive and complementary hallmarks of cancer ( Figure 3). with avoiding immune destruction [7,[67][68][69][70][71][72], invasion and metastasis [47,[73][74][75], angiogenesis [63,74,[76][77][78], resisting cell death [20,29,[79][80][81][82][83][84][85][86][87], proliferative signaling [43,52,[87][88][89][90][91][92][93][94][95][96][97][98][99], and cellular energetics [90,[100][101][102][103][104][105][106][107][108]. The activation/overexpression (green) or inactivation/subexpression (red) of those molecules consequently results in the dysregulation of a variety of key players on those hallmarks of cancer, culminating in cancer. ...
... Wang et al. [79], using a reactive oxygen species (ROS) scavenger, NAC, reported a reversion of the effects of ASCT2 knockdown Figure 3. ASCT2, LAT1, and the hallmarks of cancer. Both ASCT2 and LAT1 have been associated with avoiding immune destruction [7,[67][68][69][70][71][72], invasion and metastasis [47,[73][74][75], angiogenesis [63,74,[76][77][78], resisting cell death [20,29,[79][80][81][82][83][84][85][86][87], proliferative signaling [43,52,[87][88][89][90][91][92][93][94][95][96][97][98][99], and cellular energetics [90,[100][101][102][103][104][105][106][107][108]. The activation/overexpression (green) or inactivation/subexpression (red) of those molecules consequently results in the dysregulation of a variety of key players on those hallmarks of cancer, culminating in cancer. ...
... As previously mentioned, this amino acid can be transported into the cell by LAT1 [129]. Treatment of NSCLC cells with delta-tocotrienol (δT) inhibited both LAT1 and ASCT2 expression, resulting in a significant decrease in leucine concentration [107]. Furthermore, treatment of breast cancer cells with JPH203, a tyrosine analog and selective LAT1 inhibitor, limited the amount of leucine, and also tyrosine, that could maintain protein production or enter the TCA cycle, proving to be beneficial in combination with other mTOR inhibitors and/or endocrine therapies for breast cancer treatment [108]. ...
Article
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The role of the amino acid transporters ASCT2 and LAT1 in cancer has been explored throughout the years. In this review, we report their impact on the hallmarks of cancer, as well as their clinical significance. Overall, both proteins have been associated with cell death resistance through dysregulation of caspases and sustainment of proliferative signaling through mTOR activation. Furthermore, ASCT2 appears to play an important role in cellular energetics regulation, whereas LAT1 expression is associated with angiogenesis and invasion and metastasis activation. The molecular impact of these proteins on the hallmarks of cancer translates into various clinical applications and both transporters have been identified as prognostic factors in many types of cancer. Concerning their role as therapeutic targets, efforts have been undertaken to synthesize competitive or irreversible ASCT2 and LAT1 inhibitors. However, JHP203, a selective inhibitor of the latter, is, to the best of our knowledge, the only compound included in a Phase 1 clinical trial. In conclusion, considering the usefulness of ASCT2 and LAT1 in a variety of cancer-related pathways and cancer therapy/diagnosis, the development and testing of novel inhibitors for these transporters that could be evaluated in clinical trials represents a promising approach to cancer prognosis improvement.
... Wang et al. characterized a Gln analog called polyglutamine (PGS) to deliver therapeutic agents to Gln-addicted cancer cells and showed the importance of SLC1A5 for the cellular internalization of the small interfering RNA (siRNA)-PGS complexes [192]. Delta-tocotrienol (δT) markedly inhibits Gln uptake and leads to the reduction of Glu, GSH, and some EAAs in A549 and H1299 NSCLC cell lines by targeting SLC1A5 and SLC7A5 [171]. Thus, inhibition by δT suspends Gln metabolism, cell proliferation, and mTOR pathway, as well as induces apoptosis through the downregulation of mTOR signaling [171]. ...
... Delta-tocotrienol (δT) markedly inhibits Gln uptake and leads to the reduction of Glu, GSH, and some EAAs in A549 and H1299 NSCLC cell lines by targeting SLC1A5 and SLC7A5 [171]. Thus, inhibition by δT suspends Gln metabolism, cell proliferation, and mTOR pathway, as well as induces apoptosis through the downregulation of mTOR signaling [171]. Moreover, chemical inhibition of SLC7A5 by BCH does not inhibit melanoma cell growth, whereas SLC1A5 inhibition by BenSer reduces 2D and 3D cell proliferation and cell cycle progression. ...
Article
Full-text available
Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.
... This study showed that δ -tocotrienol treated cells were arrested in the G 0 /G 1 phase in the cell cycle, in a dose dependent manner. It has been reported that δ -tocotrienol has an inhibitory effect on proliferation of many kinds of cancer cells; [33][34][35][36][37][38] however, its effect on nasopharyngeal carcinoma was seldom examined and the molecular mechanism remains unknown. Ye δ -tocotrienol had no effect on p15, p21 and p27 expressions, and these results differ from the results in CNE1 cells in our study. ...
Article
Nasopharyngeal carcinoma has a notably high incidence rate in Southern China, Southeast Asia, North Africa, Middle East, and the Arctic. δ-tocotrienol is abundant in cereal and has some health benefits....
... The transporters capable of importing glutamine such as ATB 0,+ (SLC6A14 gene), SNAT1 (SLC38A1 gene), ASCT2 (SLC1A5 gene), LAT1 (SLC7A5 gene), and LAT2 (SLC7A8 gene) [42] are crucial in cancer metabolic remodeling often being upregulated in tumors [43][44][45][46][47]. Therefore, glutamine transport targeting is currently being addressed in pre-clinical trials. ...
Article
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Glutamine is a non-essential amino acid that plays a key role in the metabolism of proliferating cells including neoplastic cells. In the central nervous system (CNS), glutamine metabolism is particularly relevant, because the glutamine-glutamate cycle is a way of controlling the production of glutamate-derived neurotransmitters by tightly regulating the bioavailability of the amino acids in a neuron-astrocyte metabolic symbiosis-dependent manner. Glutamine-related metabolic adjustments have been reported in several CNS malignancies including malignant gliomas that are considered ‘glutamine addicted’. In these tumors, glutamine becomes an essential amino acid preferentially used in energy and biomass production including glutathione (GSH) generation, which is crucial in oxidative stress control. Therefore, in this review, we will highlight the metabolic remodeling that gliomas undergo, focusing on glutamine metabolism. We will address some therapeutic regimens including novel research attempts to target glutamine metabolism and a brief update of diagnosis strategies that take advantage of this altered profile. A better understanding of malignant glioma cell metabolism will help in the identification of new molecular targets and the design of new therapies.
... In previous studies, the selective inhibition of LAT1 by JPH203 has been demonstrated. Several groups reported that JPH203 inhibits the proliferation of cancer cells by inhibiting L-leucine uptake 13,18,26 , LAT1 has been shown to affect cancer cell proliferation through the mTOR signalling pathway in pancreatic cancer 27 , lung cancer 28 , and prostate cancer 6,29 . Leucine is an essential amino acid that must be taken from outside the cells and activates mTOR signals. ...
Article
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L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.