Amino Acid Transporter SLC6A14 (ATB0,+) – A Target in Combined Anti-cancer Therapy

Nałęcz, Katarzyna A.

doi:10.3389/fcell.2020.594464

Cited by 35 publications

(18 citation statements)

References 148 publications

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“…Consistent with these functions, the amino acid transporters SLC7A5 and SLC6A14 are upregulated in tumors, making then potential targets for the pharmacological treatment of cancer (Kanai, 2021;Nałęcz, 2020). Our experiments suggest that amino acid transporters provide amino acids that are critical for the de novo synthesis of monoamine neurotransmitters.…”

Section: Discussionsupporting

confidence: 58%

Tadr Is an Axonal Histidine Transporter Required for Visual Neurotransmission in Drosophila

Wang

Han²,

Peng³

2021

Preprint

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Neurotransmitters are generated by de novo synthesis and are essential for sustained, high-frequency synaptic transmission. Histamine, a monoamine neurotransmitter, is synthesized through decarboxylation of histidine by Histidine decarboxylase (Hdc). However, little is known about how histidine is presented to Hdc as a precursor. Here, we identified a specific histidine transporter, TADR (Torn And Diminished Rhabdomeres), that is required for visual transmission in Drosophila. TADR and Hdc co-localized to neuronal terminals, and mutations in tadr reduced levels of histamine, thus disrupting visual synaptic transmission and phototaxis behavior. These results demonstrate that a specific amino acid transporter provides precursors for monoamine neurotransmitters, providing the first genetic evidence that a histidine amino acid transporter plays a critical role in synaptic transmission. These results suggest that TADR-dependent local de novo synthesis of histamine is required for synaptic transmission.

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Section: Discussionsupporting

confidence: 58%

Tadr Is an Axonal Histidine Transporter Required for Visual Neurotransmission in Drosophila

Wang

Han²,

Peng³

2021

Preprint

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“…Plasma membrane transporters secure import of a wide range of substrates into the cytoplasm. Consistently, increased expression of several transporting proteins has been correlated to the increased metabolic activity of cancer cells and poor disease prognosis (Natecz, 2020 ; Sampedro-Núñez et al, 2020 ; Xu et al, 2020 ; Yamada et al, 2020 ).…”

Section: Introductionmentioning

confidence: 93%

Computational Model for Membrane Transporters. Potential Implications for Cancer

Carusela

Rubı́

2021

Front. Cell Dev. Biol.

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To explain the increased transport of nutrients and metabolites and to control the movement of drug molecules through the transporters to the cancer cells, it is important to understand the exact mechanism of their structure and activity, as well as their biological and physical characteristics. We propose a computational model that reproduces the functionality of membrane transporters by quantifying the flow of substrates through the cell membrane. The model identifies the force induced by conformational changes of the transporter due to hydrolysis of ATP, in ABC transporters, or by an electrochemical gradient of ions, in secondary transporters. The transport rate is computed by averaging the velocity generated by the force along the paths followed by the substrates. The results obtained are in accordance with the experiments. The model provides an overall framework for analyzing the membrane transport proteins that regulate the flows of ions, nutrients and other molecules across the cell membranes, and their activities.

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“…SLC6A14 is also known as ATB 0,+ , referring to its identity with the amino acid transport system B 0,+ (B stands for “broad-specific”; uppercase letter stands for Na + -dependence; 0,+ in the superscript stands for the ability of the transporter to accept neutral and cationic amino acids as substrates). It is energized by three driving forces: a Na + gradient, a Cl − gradient, and membrane potential [ 54 , 55 , 56 ]. Therefore, this transporter primarily mediates the influx of its substrates into cells because of the high magnitude of the combined driving forces.…”

Section: Slc6a14 and Slc38a5 And Their Relevance To Cancermentioning

confidence: 99%

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

et al. 2021

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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.

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Amino Acid Transporter SLC6A14 (ATB0,+) – A Target in Combined Anti-cancer Therapy

Cited by 35 publications

References 148 publications

Tadr Is an Axonal Histidine Transporter Required for Visual Neurotransmission in Drosophila

Tadr Is an Axonal Histidine Transporter Required for Visual Neurotransmission in Drosophila

Computational Model for Membrane Transporters. Potential Implications for Cancer

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

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