Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics—boramino acids (BAAs)—that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3−. Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

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Discovery and synthesis of hydroxy-L-proline based blockers of the neutral amino acid transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2).

10.1101/2021.12.14.470456 ◽

2021 ◽

Author(s):

Michael P Kavanaugh ◽

Brent R. Lyda ◽

Gregory P. Leary ◽

Derek Silvius ◽

Nicholas R. Natale ◽

...

Keyword(s):

Amino Acid ◽

Homology Model ◽

Neutral Amino Acid ◽

Amino Acid Transporters ◽

Biological Targets ◽

Conformationally Restricted ◽

New Class ◽

Wide Range ◽

Ligand Binding Sites ◽

Proline Derivatives

The conformationally restricted heterocycle hydroxy-ʟ-proline is a versatile scaffold for the synthesis of diverse multi-functionalized pyrrolidines for probing the ligand binding sites of biological targets. With the goal to develop new inhibitors of the widely expressed amino acid transporters SLC1A4 and SLC1A5 (also known as ASCT1 and ASCT2), we synthesized and functionally screened a series of hydroxy-ʟ-proline derivatives or 'prolinols' using electrophysiological and radio-labeled uptake assays on amino acid transporters from the SLC1, SLC7, and SLC38 solute carrier families. We identified a number of synthetic prolinols that act as selective high-affinity inhibitors of the SLC1 functional subfamily comprising the neutral amino acid transporters SLC1A4 and SLC1A5. The active and inactive prolinols were computationally docked into a threaded homology model and analyzed with respect to predicted molecular orientation and observed pharmacological activity. The series of hydroxy-L-proline derivatives identified here represents a new class of potential agents to pharmacologically modulate SLC1A4 and SLC1A5, amino acid exchangers that play important roles in a wide range of physiological and pathophysiological processes.

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Antimitotic Activity on Sea Urchin Embryonic Cells of Seven Antiparasitic Morita-Baylis-Hillman Adducts: A Potential New Class of Anticancer Drugs

Medicinal Chemistry ◽

10.2174/1573406411208061003 ◽

2012 ◽

Vol 8 (6) ◽

pp. 1003-1011

Author(s):

Jocelmo C. A. Leite ◽

Claudio G. L. Junior ◽

Fabio P. L. Silva ◽

Suervy C.O. Sousa ◽

Mario L. A. A. Vasconcellos ◽

...

Keyword(s):

Anticancer Drugs ◽

Sea Urchin ◽

Embryonic Cells ◽

New Class ◽

Antimitotic Activity

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Amino Acid Transporters on the Guard of Cell Genome and Epigenome

Cancers ◽

10.3390/cancers13010125 ◽

2021 ◽

Vol 13 (1) ◽

pp. 125

Author(s):

Uğur Kahya ◽

Ayşe Sedef Köseer ◽

Anna Dubrovska

Keyword(s):

Amino Acid ◽

Cancer Metabolism ◽

Tumor Imaging ◽

Redox Homeostasis ◽

Amino Acid Uptake ◽

Metabolic Reprogramming ◽

Tumor Evolution ◽

Amino Acid Transporters ◽

Acid Uptake ◽

Growth And Survival

Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.

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

Methods and Protocols ◽

10.3390/mps4030051 ◽

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.

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Characterization of the third member of the MCAT family of cationic amino acid transporters. Identification of a domain that determines the transport properties of the MCAT proteins.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)36854-1 ◽

1993 ◽

Vol 268 (28) ◽

pp. 20796-20800

Author(s):

E.I. Closs ◽

C.R. Lyons ◽

C Kelly ◽

J.M. Cunningham

Keyword(s):

Amino Acid ◽

Transport Properties ◽

Amino Acid Transporters ◽

Cationic Amino Acid ◽

The Third

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LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽

10.3390/biomedicines9020195 ◽

2021 ◽

Vol 9 (2) ◽

pp. 195

Author(s):

Francisca Dias ◽

Cristina Almeida ◽

Ana Luísa Teixeira ◽

Mariana Morais ◽

Rui Medeiros

Keyword(s):

Colorectal Cancer ◽

Amino Acid ◽

Cancer Progression ◽

Cell Metabolism ◽

Tumor Development ◽

Amino Acid Transporters ◽

Epigenetic Alterations ◽

Therapeutic Approaches ◽

Colorectal Cancer Progression ◽

Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

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