scholarly journals Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

2020 ◽  
Vol 21 (17) ◽  
pp. 6156 ◽  
Author(s):  
Stefan Bröer
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Protein Translation ◽  
Essential Amino Acids ◽  
Selective Vulnerability ◽  
Amino Acid Transporters ◽  
Knock Out

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.

scholarly journals The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

2018 ◽  
Vol 19 (8) ◽  
pp. 2373 ◽  
Author(s):  
Travis Salisbury ◽  
Subha Arthur
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Amino Acid Uptake ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Acid Uptake ◽  
Cancer Pathways ◽  
Acid Transporter

The progression of cancer is associated with increases in amino acid uptake by cancer cells. Upon their entry into cells through specific transporters, exogenous amino acids are used to synthesize proteins, nucleic acids and lipids and to generate ATP. The essential amino acid leucine is also important for maintaining cancer-associated signaling pathways. By upregulating amino acid transporters, cancer cells gain greater access to exogenous amino acids to support chronic proliferation, maintain metabolic pathways, and to enhance certain signal transduction pathways. Suppressing cancer growth by targeting amino acid transporters will require an in-depth understanding of how cancer cells acquire amino acids, in particular, the transporters involved and which cancer pathways are most sensitive to amino acid deprivation. L-Type Amino Acid Transporter 1 (LAT1) mediates the uptake of essential amino acids and its expression is upregulated during the progression of several cancers. We will review the upstream regulators of LAT1 and the downstream effects caused by the overexpression of LAT1 in cancer cells.

Metabolic and amino acid alterations of the tumor microenvironment

2020 ◽  
Vol 27 ◽  
Author(s):  
Petr Stepka ◽  
Vit Vsiansky ◽  
Martina Raudenska ◽  
Jaromir Gumulec ◽  
Vojtech Adam ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Amino Acids ◽  
Amino Acid ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Warburg Effect ◽  
Cell Metabolism ◽  
Metastatic Potential ◽  
Cancer Cell Metabolism

: Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely alterations in metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of prostate cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from metabolism of other tissues. Findings from different tissues are therefore not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.

scholarly journals The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

2019 ◽  
Vol 20 (10) ◽  
pp. 2428 ◽  
Author(s):  
Pascal Häfliger ◽  
Roch-Philippe Charles
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Cell Mass ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Membrane Transporters ◽  
Preclinical Studies ◽  
Acid Transporter

Chronic proliferation is a major hallmark of tumor cells. Rapidly proliferating cancer cells are highly dependent on nutrients in order to duplicate their cell mass during each cell division. In particular, essential amino acids are indispensable for proliferating cancer cells. Their uptake across the cell membrane is tightly controlled by membrane transporters. Among those, the L-type amino acid transporter LAT1 (SLC7A5) has been repeatedly found overexpressed in a vast variety of cancers. In this review, we summarize the most recent advances in our understanding of the role of LAT1 in cancer and highlight preclinical studies and drug developments underlying the potential of LAT1 as therapeutic target.

scholarly journals Coordinated Action of Multiple Transporters in the Acquisition of Essential Cationic Amino Acids by the Intracellular Parasite Toxoplasma gondii

2021 ◽  
Author(s):  
Stephen J Fairweather ◽  
Esther Rajendran ◽  
Martin Blume ◽  
Kiran Javed ◽  
Birte Steinhoefel ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Toxoplasma Gondii ◽  
Large Family ◽  
Essential Amino Acids ◽  
Amino Acid Transporters ◽  
Cationic Amino Acid ◽  
Intracellular Parasites ◽  
Cationic Amino Acids ◽  
High Concentrations

Intracellular parasites of the phylum Apicomplexa are dependent on the scavenging of essential amino acids from their hosts. We previously identified a large family of apicomplexan-specific plasma membrane-localized amino acid transporters, the ApiATs, and showed that the Toxoplasma gondii transporter TgApiAT1 functions in the selective uptake of arginine. TgApiAT1 is essential for parasite virulence, but dispensable for parasite growth in medium containing high concentrations of arginine, indicating the presence of at least one other arginine transporter. Here we identify TgApiAT6-1 as the second arginine transporter. Using a combination of parasite assays and heterologous characterisation of TgApiAT6-1 in Xenopus laevis oocytes, we demonstrate that TgApiAT6-1 is a general cationic amino acid transporter that mediates both the high-affinity uptake of lysine and the low-affinity uptake of arginine. TgApiAT6-1 is the primary lysine transporter in the disease-causing tachyzoite stage of T. gondii and is essential for parasite proliferation. We demonstrate that the uptake of cationic amino acids by TgApiAT6-1 is "trans-stimulated" by cationic and neutral amino acids and is likely promoted by an inwardly negative membrane potential. These findings demonstrate that T. gondii has evolved overlapping transport mechanisms for the uptake of essential cationic amino acids, and we draw together our findings into a comprehensive model that highlights the finely-tuned, regulated processes that mediate cationic amino acid scavenging by these intracellular parasites.

scholarly journals SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer

2021 ◽  
Vol 14 (3) ◽  
pp. 216
Author(s):  
Tyler Sniegowski ◽  
Ksenija Korac ◽  
Yangzom D. Bhutia ◽  
Vadivel Ganapathy
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Critical Role ◽  
Amino Acid Transporters ◽  
Extracellular Milieu ◽  
Methyl Transfer ◽  
Functional Features ◽  
Metabolic Reactions ◽  
Carbon Pathways

The glutaminolysis and serine–glycine–one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine–glycine–one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine–glycine–one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na+/Cl− -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na+-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy.

scholarly journals Coordinated action of multiple transporters in the acquisition of essential cationic amino acids by the intracellular parasite Toxoplasma gondii

2021 ◽  
Vol 17 (8) ◽  
pp. e1009835
Author(s):  
Stephen J. Fairweather ◽  
Esther Rajendran ◽  
Martin Blume ◽  
Kiran Javed ◽  
Birte Steinhöfel ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Toxoplasma Gondii ◽  
Large Family ◽  
Essential Amino Acids ◽  
Amino Acid Transporters ◽  
Cationic Amino Acid ◽  
Intracellular Parasites ◽  
Cationic Amino Acids ◽  
High Concentrations

Intracellular parasites of the phylum Apicomplexa are dependent on the scavenging of essential amino acids from their hosts. We previously identified a large family of apicomplexan-specific plasma membrane-localized amino acid transporters, the ApiATs, and showed that the Toxoplasma gondii transporter TgApiAT1 functions in the selective uptake of arginine. TgApiAT1 is essential for parasite virulence, but dispensable for parasite growth in medium containing high concentrations of arginine, indicating the presence of at least one other arginine transporter. Here we identify TgApiAT6-1 as the second arginine transporter. Using a combination of parasite assays and heterologous characterisation of TgApiAT6-1 in Xenopus laevis oocytes, we demonstrate that TgApiAT6-1 is a general cationic amino acid transporter that mediates both the high-affinity uptake of lysine and the low-affinity uptake of arginine. TgApiAT6-1 is the primary lysine transporter in the disease-causing tachyzoite stage of T. gondii and is essential for parasite proliferation. We demonstrate that the uptake of cationic amino acids by TgApiAT6-1 is ‘trans-stimulated’ by cationic and neutral amino acids and is likely promoted by an inwardly negative membrane potential. These findings demonstrate that T. gondii has evolved overlapping transport mechanisms for the uptake of essential cationic amino acids, and we draw together our findings into a comprehensive model that highlights the finely-tuned, regulated processes that mediate cationic amino acid scavenging by these intracellular parasites.

Screening of amino acid constituents from date palm fruits

2016 ◽  
Vol 5 (10) ◽  
pp. 4972
Author(s):  
Lata Birlangi
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
United Arab Emirates ◽  
Nutritional Value ◽  
Date Palm ◽  
Amino Acid Content ◽  
Essential Amino Acids ◽  
Cultivated Plants ◽  
Palm Fruits ◽  
Social Part

The date palm (Phoenix dactylifera L.) is one of mankind’s oldest cultivated plants. The fruit of the date palm is an important crop of the hot arid and semi-arid regions of the world. It has always played a genuine economic and social part in the lives of the people of these areas. The present objective in examining the amino acid content of different varieties of date palm fruits from Middle-East region; is to determine whether its protein could effectively supplement the nutritional value and it is also aimed in finding which variety is rich in number of amino acids. The phytochemical screening revealed the presence of eight essential amino acids and five non-essential amino acids in the date fruits. Among all the date fruit varieties taken as samples for the study, Dabbas cultivar of United Arab Emirates found to exhibit eight types of amino acids which includes five as non-essential ones. Total of thirteen amino acids were detected in the seven date cultivars. Determination of amino acid can serve as a guide to the possible nutritional value.

scholarly journals Progress towards reduced-crude protein diets for broiler chickens and sustainable chicken-meat production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sonia Yun Liu ◽  
Shemil P. Macelline ◽  
Peter V. Chrystal ◽  
Peter H. Selle
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Broiler Chickens ◽  
Crude Protein ◽  
Plasma Concentrations ◽  
Essential Amino Acids ◽  
Chicken Meat ◽  
Meat Production ◽  
Accurate Identification ◽  
Reduced Crude Protein

AbstractThe prime purpose of this review is to explore the pathways whereby progress towards reduced-crude protein (CP) diets and sustainable chicken-meat production may be best achieved. Reduced-CP broiler diets have the potential to attenuate environmental pollution from nitrogen and ammonia emissions; moreover, they have the capacity to diminish the global chicken-meat industry’s dependence on soybean meal to tangible extents. The variable impacts of reduced-CP broiler diets on apparent amino acid digestibility coefficients are addressed. The more accurate identification of amino acid requirements for broiler chickens offered reduced-CP diets is essential as this would diminish amino acid imbalances and the deamination of surplus amino acids. Deamination of amino acids increases the synthesis and excretion of uric acid for which there is a requirement for glycine, this emphasises the value of so-called “non-essential” amino acids. Starch digestive dynamics and their possible impact of glucose on pancreatic secretions of insulin are discussed, although the functions of insulin in avian species require clarification. Maize is probably a superior feed grain to wheat as the basis of reduced-CP diets; if so, the identification of the underlying reasons for this difference should be instructive. Moderating increases in starch concentrations and condensing dietary starch:protein ratios in reduced-CP diets may prove to be advantageous as expanding ratios appear to be aligned to inferior broiler performance. Threonine is specifically examined because elevated free threonine plasma concentrations in birds offered reduced-CP diets may be indicative of compromised performance. If progress in these directions can be realised, then the prospects of reduced-CP diets contributing to sustainable chicken-meat production are promising.

scholarly journals Further evidence that mechanisms of host/symbiont integration are dissimilar in the maternal versus embryonic Acyrthosiphon pisum bacteriome

EvoDevo ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Celeste R. Banfill ◽  
Alex C. C. Wilson ◽  
Hsiao-ling Lu
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Acyrthosiphon Pisum ◽  
Essential Amino Acids ◽  
Developmental Time ◽  
Follicular Epithelium ◽  
Future Research ◽  
Buchnera Aphidicola ◽  
Bacterial Endosymbionts ◽  
Asexual Embryogenesis

Abstract Background Host/symbiont integration is a signature of evolutionarily ancient, obligate endosymbioses. However, little is known about the cellular and developmental mechanisms of host/symbiont integration at the molecular level. Many insects possess obligate bacterial endosymbionts that provide essential nutrients. To advance understanding of the developmental and metabolic integration of hosts and endosymbionts, we track the localization of a non-essential amino acid transporter, ApNEAAT1, across asexual embryogenesis in the aphid, Acyrthosiphon pisum. Previous work in adult bacteriomes revealed that ApNEAAT1 functions to exchange non-essential amino acids at the A. pisum/Buchnera aphidicola symbiotic interface. Driven by amino acid concentration gradients, ApNEAAT1 moves proline, serine, and alanine from A. pisum to Buchnera and cysteine from Buchnera to A. pisum. Here, we test the hypothesis that ApNEAAT1 is localized to the symbiotic interface during asexual embryogenesis. Results During A. pisum asexual embryogenesis, ApNEAAT1 does not localize to the symbiotic interface. We observed ApNEAAT1 localization to the maternal follicular epithelium, the germline, and, in late-stage embryos, to anterior neural structures and insect immune cells (hemocytes). We predict that ApNEAAT1 provisions non-essential amino acids to developing oocytes and embryos, as well as to the brain and related neural structures. Additionally, ApNEAAT1 may perform roles related to host immunity. Conclusions Our work provides further evidence that the embryonic and adult bacteriomes of asexual A. pisum are not equivalent. Future research is needed to elucidate the developmental time point at which the bacteriome reaches maturity.

The screening and preliminary construction of quality mutant population for cultivar “Nipponbare” in japonica rice (Oryza sativa)

Biologia ◽  
2012 ◽  
Vol 67 (6) ◽  
Author(s):  
Da Zhang ◽  
Jian Wu ◽  
Guan Li ◽  
Chun Shi
Keyword(s):  
Amino Acids ◽  
Oryza Sativa ◽  
Amino Acid ◽  
Mutation Frequency ◽  
Near Infrared ◽  
Essential Amino Acids ◽  
Japonica Rice ◽  
Near Infrared Reflectance ◽  
Mutant Population ◽  
Nonessential Amino Acids

AbstractProgenies of Oryza sativa cv. Nipponbare induced with 0.4% ethyl methane sulphonate (EMS) were screened for quality mutants and the preliminary quality mutant population was constructed in present experiment. A total of 2210 materials were first screened using near infrared reflectance spectroscopy (NIRS) from which 208 quality mutants were obtained for a second screening and then yielded 73 quality mutants including amylase content (AC), gel consistency (GC), gelatinization temperature (GT), protein content (PC), rapid viscosity analysis (RVA) parameters and amino acid contents. The screening yielded 11 PC mutants with a mutation frequency of 4.98‰, followed by 7 rice floury viscosity mutants (3.17‰), 5 AC mutants (2.26‰), 4 chalky mutants, GT and GC mutants (1.81‰), and 2 ASV mutants (0.9‰). The relative contents of 17 kinds of amino acid mutations, including 7 kinds for essential amino acids and 10 kinds for nonessential amino acids were identified. With the variation of 10% as the screening standard, mutants were obtained for lysine and leucine at 0.45‰ and for valine at 4.98‰, but no mutants were found for isoleucine, phenylalanine, threonine. For nonessential amino acids, mutants of glutamic (0.45‰), arginine (3.62‰), alanine (3.17‰), serine (0.45‰), glycine (0.45‰), tyrosine (1.81‰), proline (2.71‰), and histidine (0.45‰) were obtained, but none was found for aspartic, phenylalanine nor threonine. At 100% as the screening standard for methionine and cysteines, the mutation frequency of these two amino acid mutants were 0.9‰ and 4.98‰ respectively. Quality mutants in this preliminary library of rice could play important role in gene function and breeding of rice quality.

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