L-Type amino acid transporter 1 as a target for drug delivery

Puris, Elena; Gynther, Mikko; Auriola, Seppo; Huttunen, Kristiina M.

doi:10.1007/s11095-020-02826-8

Cited by 115 publications

(104 citation statements)

References 110 publications

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“…Notably, a recent study found that LAT1 was a pH-dependent but not pH-independent transporter, whose maximal transporter activity is at neutral pH but much lower at acidic pH (Cosco et al, 2020 ). LAT1 ( SLC7A5 ) imports BCAAs and several essential amino acids (e.g., phenylalanine, leucine, isoleucine, tryptophan, histidine, and tyrosine) with high affinity in exchange for the efflux of intracellular histidine, tyrosine, and glutamine (Nicklin et al, 2009 ; Puris et al, 2020 ). To maintain amino acid nutrition for tumor growth, the expression of the LAT1 ( SLC7A5 ) transporter is controlled by the pro-carcinogenic transcription factors c-Myc (Yue et al, 2017 ), HIF2α (Elorza et al, 2012 ), and NOTCH (Grzes et al, 2017 ), as well as the post-transcriptional regulator miR-126 (Miko et al, 2011 ).…”

Section: Amino Acid Metabolism In Cancermentioning

confidence: 99%

Metabolism of Amino Acids in Cancer

Wei

Liu

Cheng

et al. 2021

Front. Cell Dev. Biol.

223

193

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Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism of amino acids are aberrantly upregulated in many cancers that display addiction to particular amino acids. Amino acids facilitate the survival and proliferation of cancer cells under genotoxic, oxidative, and nutritional stress. Thus, targeting amino acid metabolism is becoming a potential therapeutic strategy for cancer patients. In this review, we will systematically summarize the recent progress of amino acid metabolism in malignancy and discuss their interconnection with mammalian target of rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth and immunity, and ferroptosis. Finally, we will highlight the potential therapeutic applications.

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Section: Amino Acid Metabolism In Cancermentioning

confidence: 99%

Metabolism of Amino Acids in Cancer

Wei

Liu

Cheng

et al. 2021

Front. Cell Dev. Biol.

223

193

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“…4F2hc-LAT1 is expressed in different tissues and organs (e.g., brain, ovary, placenta and testis), and in relatively high levels at the blood-brain barrier and in several types of tumors (Fotiadis et al, 2013;Scalise et al, 2018;Häfliger and Charles, 2019). The location and high expression levels make 4F2hc-LAT1 an interesting vehicle for drug delivery into the brain and for cancer cell targeting (Häfliger and Charles, 2019;Puris et al, 2020). In cancer cells, 4F2hc-LAT1 provides neutral and essential amino acids for nutrition and regulation of the mTOR signaling pathway (Nicklin et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Yeast Cell-Based Transport Assay for the Functional Characterization of Human 4F2hc-LAT1 and ‐LAT2, and LAT1 and LAT2 Substrates and Inhibitors

Kantipudi

Fotiadis

2021

Front. Mol. Biosci.

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In mammalian cells, the L-type amino acid transporters (LATs) LAT1 (SLC7A5) and LAT2 (SLC7A8) form heterodimeric amino acid transporters (HATs) with the ancillary protein 4F2hc and are involved in the cellular uptake of specific amino acids. The HAT 4F2hc-LAT1 is found upregulated in various cancer cell types, while 4F2hc-LAT2 is a transporter for non-cancer cells. Preclinical studies have highlighted that 4F2hc-LAT1 plays an important role in tumor progression representing a valid anticancer target. Consequently, current research is focusing on the development of potent and specific human 4F2hc-LAT1 inhibitors. On the other hand, 4F2hc-LAT2 is emerging as target of other diseases, thus also gaining clinical interest. To determine affinity and specificity of substrates and inhibitors for 4F2hc-LAT1 or 4F2hc-LAT2, robust transport cell assays are indispensable. We have optimized and validated a transport assay using cells of the methylotrophic yeast Pichia pastoris stably overexpressing the human HATs 4F2hc-LAT1 or -LAT2, and the LATs LAT1 or LAT2 alone. The radioligand [3H]L-leucine was used as reporter and the substrates L-leucine, triiodothyronine (T3) and thyroxine (T4) as well as the inhibitors BCH and JPH203 (KYT-0353) for assay validation. Obtained half-maximal inhibitory concentrations also provided new insights, e.g., into the LAT specificity of the potent inhibitor JPH203 and on the potency of the thyroid hormones T3 and T4 to inhibit transport through human 4F2hc-LAT2. The LAT1 and LAT2 assays are of particular interest to determine possible implications and influences of 4F2hc in ligand binding and transport. In summary, the presented assays are valuable for characterization of ligands, e.g., towards 4F2hc-LAT1 specificity, and can also be applied for compound screening. Finally, our established approach and assay would also be applicable to other HATs and LATs of interest.

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“…Relative high concentrations in L-leucine result in increased mammalian target of rapamycin (mTOR) activation [ 17 ], which supports growth and survival of cancer cells [ 18 ]. Because of its localization in the blood-brain barrier, 4F2hc-LAT1 is a promising transport system, which is also utilized to shuttle drugs and prodrugs into the brain [ 19 ]. Recently, it was suggested that lack or defects in LAT2 are implicated in age-related hearing loss [ 20 ] and cataract formation [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

The Heavy Chain 4F2hc Modulates the Substrate Affinity and Specificity of the Light Chains LAT1 and LAT2

Kantipudi

Jeckelmann

Ucurum

et al. 2020

IJMS

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The human L-type amino acid transporters LAT1 and LAT2 mediate the transport of amino acids and amino acid derivatives across plasma membranes in a sodium-independent, obligatory antiport mode. In mammalian cells, LAT1 and LAT2 associate with the type-II membrane N-glycoprotein 4F2hc to form heteromeric amino acid transporters (HATs). The glycosylated ancillary protein 4F2hc is known to be important for successful trafficking of the unglycosylated transporters to the plasma membrane. The heavy (i.e., 4F2hc) and light (i.e., LAT1 and LAT2) chains belong to the solute carrier (SLC) families SLC3 and SLC7, and are covalently linked by a conserved disulfide bridge. Overexpression, absence, or malfunction of certain HATs is associated with human diseases and HATs are therefore considered therapeutic targets. Here, we present a comparative, functional characterization of the HATs 4F2hc-LAT1 and 4F2hc-LAT2, and their light chains LAT1 and LAT2. For this purpose, the HATs and the light chains were expressed in the methylotrophic yeast Pichia pastoris and a radiolabel transport assay was established. Importantly and in contrast to mammalian cells, P. pastoris has proven useful as eukaryotic expression system to successfully express human LAT1 and LAT2 in the plasma membrane without the requirement of co-expressed trafficking chaperone 4F2hc. Our results show a novel function of the heavy chain 4F2hc that impacts transport by modulating the substrate affinity and specificity of corresponding LATs. In addition, the presented data confirm that the light chains LAT1 and LAT2 constitute the substrate-transporting subunits of the HATs, and that light chains are also functional in the absence of the ancillary protein 4F2hc.

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L-Type amino acid transporter 1 as a target for drug delivery

Cited by 115 publications

References 110 publications

Metabolism of Amino Acids in Cancer

Metabolism of Amino Acids in Cancer

Yeast Cell-Based Transport Assay for the Functional Characterization of Human 4F2hc-LAT1 and ‐LAT2, and LAT1 and LAT2 Substrates and Inhibitors

The Heavy Chain 4F2hc Modulates the Substrate Affinity and Specificity of the Light Chains LAT1 and LAT2

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