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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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... 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

... 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]. ...
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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.
... 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.
... Delta-tocotrienol (δT) is one of the isomers of vitamin E with antineoplastic property. To explore underlying action mechanism, a 1 H-NMR-based metabolomics of A549 and H1299 cells in vitro was used [71]. In detail, δT treatment could suppress the glutamine uptake via suppressing glutamine transporters and then resulted in the induction of apoptosis and suppression of cell proliferation. ...
Article
Background The solute carrier family 7 (SLC7) family can be categorically divided into two subfamilies, the L-type amino acid transporters (LATs) including SLC7A5-13, and SLC7A15, and the cationic amino acid transporters (CATs) including SLC7A1-4 and SLC7A14. Members of the CAT family transport predominantly cationic amino acids by facilitated diffusion with intracellular substrates. LAT1 (also known as SLC7A5), is defined as heteromeric amino acid transporter (HAT) interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide to uptake not only large neutral amino acids, but also several pharmaceutical drugs to cells. Methods In this review, we provide an overview of the interaction of the structure-function of LAT1 and its essential role in cancer. Specifically, its role at the blood-brain barrier (BBB) to facilitate the transport of thyroid hormones, pharmaceuticals (e.g.,I-DOPA, gabapentin), and metabolites into the brain. Results LAT1 expression increases as cancers progress, leading to higher expression levels in high-grade tumors and metastases. In addition, LAT1 plays a crucial role in cancer-associated reprogrammed metabolic networks by supplying tumor cells with essential amino acids. Conclusions The increasing understanding of the role of LAT1 in cancer has led to an increase in interest surrounding its potential as a drug target for cancer treatment.
Article
α-Tocopherol (α-T) is the major form of vitamin E (VE) in animals and has the highest activity in carrying out the essential antioxidant functions of VE. Because of the involvement of oxidative stress in carcinogenesis, the cancer prevention activity of α-T has been studied extensively. Lower VE intake or nutritional status has been shown to be associated with increased cancer risk, and supplementation of α-T to populations with VE insufficiency has shown beneficial effects in lowering the cancer risk in some intervention studies. However, several large intervention studies with α-T conducted in North America have not demonstrated a cancer prevention effect. More recent studies have centered on the γ- and δ-forms of tocopherols and tocotrienols (T3). In comparison with α-T, these forms have much lower systemic bioavailability but have shown stronger cancer-preventive activities in many studies in animal models and cell lines. γ-T3 and δ-T3 generally have even higher activities than γ-T and δ-T. In this article, we review recent results from human and laboratory studies on the cancer-preventive activities of different forms of tocopherols and tocotrienols, at nutritional and pharmacological levels. We aim to elucidate the possible mechanisms of the preventive actions and discuss the possible application of the available information for human cancer prevention by different VE forms.
Chapter
The microenvironment depends and generates dependence on all the cells and structures that share the same niche, the biotope. The contemporaneous view of the tumor microenvironment (TME) agrees with this idea. The cells that make up the tumor, whether malignant or not, behave similarly to classes of elements within a living community. These elements inhabit, modify and benefit from all the facilities the microenvironment has to offer and that will contribute to the survival and growth of the tumor and the progression of the disease.
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Circular RNAs (circRNAs) are closely associated with the development of non-small cell lung cancer (NSCLC); however, it is still unclear whether circular RNA circ-LDLRAD3 participated in the regulation of NSCLC progression. In this study, we found that circ-LDLRAD3 was high-expressed and miR-137 was low-expressed in NSCLC tissues and cells compared to their normal counterparts, which showed negative correlations in NSCLC tissues. Further experiments validated that miR-137 could be sponged and inhibited by circ-LDLRAD3 in NSCLC cells. In addition, knock-down of circ-LDLRAD3 and miR-137 overexpression promoted NSCLC cell apoptosis, and inhibited cell proliferation and invasion. Similarly, upregulation of circ-LDLRAD3 or miR-137 ablation had opposite effects on the above cell functions. Besides, the glutamine transporter SLC1A5 was validated to be the downstream target of circ-LDLRAD3 and miR-137, and upregulated circ-LDLRAD3 increased SLC1A5 expression levels by downregulating miR-137. Furthermore, the effects of downregulated circ-LDLRAD3 on cell proliferation, apoptosis and mobility were all reversed by knocking down miR-137 and overexpressing SLC1A5. Taken together, this in vitro study found that knock-down of circ-LDLRAD3 inhibited the development of NSCLC by regulating miR-137/SLC1A5 axis.
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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.