Internalization into cancer cells of zwitterionic amino acid polymers via amino acid transporter recognition

2021 ◽  
Author(s):  
Shin Takano ◽  
Kazuo Sakurai ◽  
Shota Fujii
Keyword(s):  
Amino Acid ◽  
Cancer Cells ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Acid Transporter ◽  
Amino Acid Polymers ◽  
Recognition Capability

We synthesized lysine- and phenylalanine-based zwitterionic amino acid polymers (ZAPs) and evaluated their recognition capability for amino acid transporters (AATs), which are overexpressed on cancer cells as compared with normal...

scholarly journals Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2608 ◽  
Author(s):  
Sungwoo Hong ◽  
Zhenghuan Fang ◽  
Hoi-Yun Jung ◽  
Jin-Ha Yoon ◽  
Soon-Sun Hong ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Amino Acid ◽  
Cancer Cells ◽  
Systemic Exposure ◽  
Amino Acid Transporter ◽  
Amide Bond ◽  
Amino Acid Transporters ◽  
Pancreatic Cancer Cells ◽  
Acid Transporter

To investigate the amino acid transporter-based prodrug anticancer strategy further, several amino acid-conjugated amide gemcitabine prodrugs were synthesized to target amino acid transporters in pancreatic cancer cells. The structures of the synthesized amino acid-conjugated prodrugs were confirmed by 1H-NMR and LC-MS. The pancreatic cancer cells, AsPC1, BxPC-3, PANC-1 and MIAPaCa-2, appeared to overexpress the amino acid transporter LAT-1 by conventional RT-PCR. Among the six amino acid derivatives of gemcitabine, threonine derivative of gemcitabine (Gem-Thr) was more effective than free gemcitabine in the pancreatic cancer cells, BxPC-3 and MIAPaCa-2, respectively, in terms of anti-cancer effects. Furthermore, Gem-Thr was metabolically stable in PBS (pH 7.4), rat plasma and liver microsomal fractions. When Gem-Thr was administered to rats at 4 mg/kg i.v., Gem-Thr was found to be successfully converted to gemcitabine via amide bond cleavage. Moreover, the Gem-Thr showed the increased systemic exposure of formed gemcitabine by 1.83-fold, compared to free gemcitabine treatment, due to the significantly decreased total clearance (0.60 vs. 4.23 mL/min/kg), indicating that the amide prodrug approach improves the metabolic stability of gemcitabine in vivo. Taken together, the amino acid transporter-targeting gemcitabine prodrug, Gem-Thr, was found to be effective on pancreatic cancer cells and to offer an efficient potential means of treating pancreatic cancer with significantly better pharmacokinetic characteristics than gemcitabine.

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.

scholarly journals Pichia pastoris and the Recombinant Human Heterodimeric Amino Acid Transporter 4F2hc-LAT1: From Clone Selection to Pure Protein

2021 ◽  
Vol 4 (3) ◽  
pp. 51
Author(s):  
Satish Kantipudi ◽  
Daniel Harder ◽  
Sara Bonetti ◽  
Dimitrios Fotiadis ◽  
Jean-Marc Jeckelmann
Keyword(s):  
Amino Acid ◽  
Pichia Pastoris ◽  
Protein Complexes ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Expression Host ◽  
Amino Acids And Derivatives ◽  
Heterodimeric Complex ◽  
Acid Transporter ◽  
And Function

Heterodimeric amino acid transporters (HATs) are protein complexes composed of two subunits, a heavy and a light subunit belonging to the solute carrier (SLC) families SLC3 and SLC7. HATs transport amino acids and derivatives thereof across the plasma membrane. The human HAT 4F2hc-LAT1 is composed of the type-II membrane N-glycoprotein 4F2hc (SLC3A2) and the L-type amino acid transporter LAT1 (SLC7A5). 4F2hc-LAT1 is medically relevant, and its dysfunction and overexpression are associated with autism and tumor progression. Here, we provide a general applicable protocol on how to screen for the best membrane transport protein-expressing clone in terms of protein amount and function using Pichia pastoris as expression host. Furthermore, we describe an overexpression and purification procedure for the production of the HAT 4F2hc-LAT1. The isolated heterodimeric complex is pure, correctly assembled, stable, binds the substrate L-leucine, and is thus properly folded. Therefore, this Pichia pastoris-derived recombinant human 4F2hc-LAT1 sample can be used for downstream biochemical and biophysical characterizations.

scholarly journals Comparative phosphoproteomics between non-competitive and competitive inhibitions of L-type amino acid transporter 1 in cancer cells.

2019 ◽  
Vol 92 (0) ◽  
pp. 1-P-106
Author(s):  
Pornparn Kongpracha ◽  
Pattama Wiriyasermkul ◽  
Yoko Tanaka ◽  
Suguru Okuda ◽  
Ryuichi Ohgaki ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cancer Cells ◽  
Amino Acid Transporter ◽  
Acid Transporter

scholarly journals Anti‐tumor effects of an antagonistic mAb against the ASCT2 amino acid transporter on KRAS ‐mutated human colorectal cancer cells

2019 ◽  
Vol 9 (1) ◽  
pp. 302-312 ◽  
Author(s):  
Yuta Hara ◽  
Yushi Minami ◽  
Soshi Yoshimoto ◽  
Natsumi Hayashi ◽  
Akitaka Yamasaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Amino Acid ◽  
Cancer Cells ◽  
Amino Acid Transporter ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cells ◽  
Acid Transporter ◽  
Human Colorectal Cancer Cells

scholarly journals Downregulation of Placental Amino Acid Transporter Expression and mTORC1 Signaling Activity Contributes to Fetal Growth Retardation in Diabetic Rats

2020 ◽  
Vol 21 (5) ◽  
pp. 1849
Author(s):  
Jie Xu ◽  
Jiao Wang ◽  
Yang Cao ◽  
Xiaotong Jia ◽  
Yujia Huang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rat Model ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Amino Acid Transport System ◽  
Intrauterine Growth ◽  
System L ◽  
Acid Transporter ◽  
Transporter Expression

Alterations in placental transport may contribute to abnormal fetal intrauterine growth in pregnancies complicated by diabetes, but it is not clear whether the placental amino acid transport system is altered in diabetic pregnancies. We therefore studied the changes in the expressions of placental amino acid transporters in a rat model of diabetes induced by streptozotocin, and tested the effects of hyperglycemia on trophoblast amino acid transporter in vitro. Our results showed that the expressions for key isoforms of system L amino acid transporters were significantly reduced in the placentas of streptozotocin-induced diabetic pregnant rats, which was associated with the decreased birthweight in the rats. A decreased placental efficiency and decreased placental mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity were also found in the rat model. In addition, hyperglycemia in vitro could inhibit amino acid transporter expression and mTORC1 activity in human trophoblast. Inhibition of mTORC1 activity led to reduced amino acid transporter expression in placental trophoblast. We concluded that reduced placental mTORC1 activity during pregnancy resulted in decreased placental amino acid transporter expression and, subsequently, contributed to fetal intrauterine growth restriction in pregnancies complicated with diabetes.

scholarly journals Amino Acid Transport Defects in Human Inherited Metabolic Disorders

2019 ◽  
Vol 21 (1) ◽  
pp. 119 ◽  
Author(s):  
Raquel Yahyaoui ◽  
Javier Pérez-Frías
Keyword(s):  
Amino Acid ◽  
Metabolic Disorders ◽  
Strong Association ◽  
Cell Types ◽  
Amino Acid Transporter ◽  
Molecular Defect ◽  
Amino Acid Transporters ◽  
Inherited Disorders ◽  
Laboratory Findings ◽  
Acid Transporter

Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future.

Sign in / Sign up

Export Citation Format

Share Document