SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

Palazzolo, Luca; Paravicini, Chiara; Laurenzi, Tommaso; Adobati, Sara; Saporiti, Simona; Guerrini, Uliano; Gianazza, Elisabetta; Indiveri, Cesare; Anderson, Catriona M.H.; Thwaites, David T.; Eberini, Ivano

doi:10.1177/2472555219867317

Cited by 20 publications

(22 citation statements)

References 42 publications

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“…SLC6A14 was not crystallized, anyhow, it has been predicted to have a core structure of the bacterial LeuT transporter (Yamashita et al, 2005). Recently, however, the structural model was proposed using a chimeric model based on the crystal structure of Drosophila DAT and the structure of phosphofructokinase from S. cerevisiae, as a model for the second extracellular loop (Palazzolo et al, 2019). Using the molecular dynamics simulation and a molecular docking procedure with SLC6A14 substrates, the authors presented a model with 2 binding sites for substrates/inhibitor (S1 and S2) and co-transported ions (Na1 and Na2).…”

Section: Slc6a14 -A Transporter With Broad Substrate Specificitymentioning

confidence: 99%

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

Nałęcz

2020

Front. Cell Dev. Biol.

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Cancer cells are characterized by quick growth and proliferation, demanding constant supply of various nutrients. Several plasma membrane transporters delivering such compounds are upregulated in cancer. Solute carrier family 6 member 14 (SLC6A14), known as amino acid transporter B 0,+ (ATB 0,+) transports all amino acids with exception of the acidic ones: aspartate and glutamate. Its malfunctioning is correlated with several pathological states and it is upregulated in solid tumors. The high expression of SLC6A14 is prognostic and unfavorable in pancreatic cancer, while in breast cancer it is expressed in estrogen receptor positive cells. As many plasma membrane transporters it resides in endoplasmic reticulum (ER) membrane after translation before further trafficking through Golgi to the cell surface. Transporter exit from ER is strictly controlled. The proper folding of SLC6A14 was shown to be controlled from the cytoplasmic side by heat shock proteins, further exit from ER and formation of coatomer II (COPII) coated vesicles depends on specific interaction with COPII cargo-recognizing subunit SEC24C, phosphorylated by kinase AKT. Inhibition of heat shock proteins, known to be upregulated in cancer, directs SLC6A14 to degradation. Targeting proteins regulating SLC6A14 trafficking is proposed as an additional pharmacological treatment of cancer.

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Section: Slc6a14 -A Transporter With Broad Substrate Specificitymentioning

confidence: 99%

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

Nałęcz

2020

Front. Cell Dev. Biol.

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“…However, the recently solved 3D structure of SLC6A19 [158], that belongs to the same family, may furnish some clues to improve the ATB 0,+ homology model as it has been recently described by a computational approach [159].…”

Section: Slc6a14: Concentrative Transporter For Amino Acids In Cancermentioning

confidence: 99%

Membrane Transporters for Amino Acids as Players of Cancer Metabolic Rewiring

Scalise

Console

Rovella

et al. 2020

Cells

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Cancer cells perform a metabolic rewiring to sustain an increased growth rate and compensate for the redox stress caused by augmented energy metabolism. The metabolic changes are not the same in all cancers. Some features, however, are considered hallmarks of this disease. As an example, all cancer cells rewire the amino acid metabolism for fulfilling both the energy demand and the changed signaling routes. In these altered conditions, some amino acids are more frequently used than others. In any case, the prerequisite for amino acid utilization is the presence of specific transporters in the cell membrane that can guarantee the absorption and the traffic of amino acids among tissues. Tumor cells preferentially use some of these transporters for satisfying their needs. The evidence for this phenomenon is the over-expression of selected transporters, associated with specific cancer types. The knowledge of the link between the over-expression and the metabolic rewiring is crucial for understanding the molecular mechanism of reprogramming in cancer cells. The continuous growth of information on structure–function relationships and the regulation of transporters will open novel perspectives in the fight against human cancers.

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“…This latter transporter also belongs to the solute carrier superfamily and shows 46% amino acid identity and 62% similarity to SLC6A14. Most recently, structural modeling of the human SLC6A14, docking and molecular dynamics studies were undertaken; this study unraveled novel aspects of the human SLC6A14 structure-function relationship, thereby having important implications for cancer treatment through the future design of novel inhibitors of SLC6A14-mediated transport [28].…”

Section: Docking Studiesmentioning

confidence: 99%

Naphthol-derived Betti bases as potential SLC6A14 blockers

Puerta¹,

Alexis²,

Abdilla³

et al. 2019

J. Mol. Clin. Med.

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Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI 50 ) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na + -and Cl − -dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α-methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJ-hTERT.

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SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

Cited by 20 publications

References 42 publications

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

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

Membrane Transporters for Amino Acids as Players of Cancer Metabolic Rewiring

Naphthol-derived Betti bases as potential SLC6A14 blockers

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