Proximal-type epithelioid sarcoma in pubic region expressing L-type amino acid transporter 1: A case report

Proximal-type epithelioid sarcoma is an aggressive malignant soft-tissue neoplasm, a “proximal” variant of epithelioid sarcoma, resistant to multimodal therapy and involved in early tumor-related death. Pertinent treatments are, therefore, continually being explored. A 24-year-old woman with nonmetastatic proximal-type epithelioid sarcoma, originating subcutaneously on the right side of the vulva, underwent surgical resection; the lesion recurred, however, leading to death 3 months after the second surgery. Here described is a case of proximal-type epithelioid sarcoma expressing L-type amino acid transporter 1 (LAT1) that transports essential amino acids and p-borono-L-phenylalanine (BPA)—the chemical compound used in boron neutron capture therapy (BNCT)—and is highly expressed in many malignant tumors. Recently, LAT1 has drawn attention, and relevant treatments have been studied—LAT1 inhibitor and BNCT. LAT1 expression in proximal-type epithelioid sarcoma may lead to cogent treatments for the disease.

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Enhancement of Cancer Cell-Killing Effects of Boron Neutron Capture Therapy by Manipulating the Expression of L-Type Amino Acid Transporter 1

Radiation Research ◽

10.1667/rade-20-00214.1 ◽

2021 ◽

Vol 196 (1) ◽

Author(s):

Ken Ohnishi ◽

Masaki Misawa ◽

Naoto Sikano ◽

Kei Nakai ◽

Minoru Suzuki

Keyword(s):

Amino Acid ◽

Cancer Cell ◽

Boron Neutron Capture Therapy ◽

Neutron Capture ◽

Amino Acid Transporter ◽

Cell Killing ◽

Neutron Capture Therapy ◽

Boron Neutron Capture ◽

Acid Transporter

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l-Amino Acid Transporter-1 and Boronophenylalanine-Based Boron Neutron Capture Therapy of Human Brain Tumors

Cancer Research ◽

10.1158/0008-5472.can-08-2345 ◽

2009 ◽

Vol 69 (5) ◽

pp. 2126-2132 ◽

Cited By ~ 57

Author(s):

Allah Detta ◽

Garth S. Cruickshank

Keyword(s):

Amino Acid ◽

Brain Tumors ◽

Human Brain ◽

Boron Neutron Capture Therapy ◽

Neutron Capture ◽

Amino Acid Transporter ◽

Neutron Capture Therapy ◽

Human Brain Tumors ◽

Boron Neutron Capture ◽

Acid Transporter

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The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20102428 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2428 ◽

Cited By ~ 33

Author(s):

Pascal Häfliger ◽

Roch-Philippe Charles

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Cancer Cells ◽

Cell Mass ◽

Essential Amino Acids ◽

Amino Acid Transporter ◽

Membrane Transporters ◽

Preclinical Studies ◽

Acid Transporter

Chronic proliferation is a major hallmark of tumor cells. Rapidly proliferating cancer cells are highly dependent on nutrients in order to duplicate their cell mass during each cell division. In particular, essential amino acids are indispensable for proliferating cancer cells. Their uptake across the cell membrane is tightly controlled by membrane transporters. Among those, the L-type amino acid transporter LAT1 (SLC7A5) has been repeatedly found overexpressed in a vast variety of cancers. In this review, we summarize the most recent advances in our understanding of the role of LAT1 in cancer and highlight preclinical studies and drug developments underlying the potential of LAT1 as therapeutic target.

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Ubiquitylation and endocytosis of the human LAT1/SLC7A5 amino acid transporter

Scientific Reports ◽

10.1038/s41598-019-53065-w ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Céline Barthelemy ◽

Bruno André

Keyword(s):

Amino Acids ◽

Plasma Membrane ◽

Protein Kinase C ◽

Amino Acid ◽

Ubiquitin Ligase ◽

Essential Amino Acids ◽

Amino Acid Transporter ◽

Kinase C ◽

Acid Transporter ◽

Mtorc1 Activation

AbstractThe human L-type amino acid transporter 1 (LAT1), also known as SLC7A5, catalyzes the transport of large neutral amino acids across the plasma membrane. As the main transporter of several essential amino acids, notably leucine, LAT1 plays an important role in mTORC1 activation. Furthermore, it is overexpressed in various types of cancer cells, where it contributes importantly to sustained growth. Despite the importance of LAT1 in normal and tumor cells, little is known about the mechanisms that might control its activity, for example by promoting its downregulation via endocytosis. Here we report that in HeLa cells, activation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) triggers efficient endocytosis and degradation of LAT1. Under these conditions we found LAT1 downregulation to correlate with increased LAT1 ubiquitylation. This modification was considerably reduced in cells depleted of the Nedd4-2 ubiquitin ligase. By systematically mutagenizing the residues of the LAT1 cytosolic tails, we identified a group of three close lysines (K19, K25, K30) in the N-terminal tail that are important for PMA-induced ubiquitylation and downregulation. Our study thus unravels a mechanism of induced endocytosis of LAT1 elicited by Nedd4-2-mediated ubiquitylation of the transporter’s N-terminal tail.

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JNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila

PLoS Genetics ◽

10.1371/journal.pgen.1009893 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1009893

Author(s):

Bojie Cong ◽

Mai Nakamura ◽

Yukari Sando ◽

Takefumi Kondo ◽

Shizue Ohsawa ◽

...

Keyword(s):

Drug Resistance ◽

Amino Acid ◽

Tumor Growth ◽

Cancer Progression ◽

Genetic Model ◽

Malignant Tumors ◽

Amino Acid Transporter ◽

Rnai Screen ◽

Oncogenic Mutations ◽

Acid Transporter

Identifying a common oncogenesis pathway among tumors with different oncogenic mutations is critical for developing anti-cancer strategies. Here, we performed transcriptome analyses on two different models of Drosophila malignant tumors caused by Ras activation with cell polarity defects (RasV12/scrib-/-) or by microRNA bantam overexpression with endocytic defects (bantam/rab5-/-), followed by an RNAi screen for genes commonly essential for tumor growth and malignancy. We identified that Juvenile hormone Inducible-21 (JhI-21), a Drosophila homolog of the L-amino acid transporter 1 (LAT1), is upregulated in these malignant tumors with different oncogenic mutations and knocking down of JhI-21 strongly blocked their growth and invasion. JhI-21 expression was induced by simultaneous activation of c-Jun N-terminal kinase (JNK) and Yorkie (Yki) in these tumors and thereby contributed to tumor growth and progression by activating the mTOR-S6 pathway. Pharmacological inhibition of LAT1 activity in Drosophila larvae significantly suppressed growth of RasV12/scrib-/- tumors. Intriguingly, LAT1 inhibitory drugs did not suppress growth of bantam/rab5-/- tumors and overexpression of bantam rendered RasV12/scrib-/- tumors unresponsive to LAT1 inhibitors. Further analyses with RNA sequencing of bantam-expressing clones followed by an RNAi screen suggested that bantam induces drug resistance against LAT1 inhibitors via downregulation of the TMEM135-like gene CG31157. Our observations unveil an evolutionarily conserved role of LAT1 induction in driving Drosophila tumor malignancy and provide a powerful genetic model for studying cancer progression and drug resistance.

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Chemical Approaches for Studying the Biology and Pharmacology of Membrane Transporters: The Histidine/Large Amino Acid Transporter SLC7A5 as a Benchmark

Molecules ◽

10.3390/molecules26216562 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6562

Author(s):

Mariafrancesca Scalise ◽

Raffaella Scanga ◽

Lara Console ◽

Michele Galluccio ◽

Lorena Pochini ◽

...

Keyword(s):

Amino Acid ◽

Essential Amino Acids ◽

Amino Acid Transporter ◽

Membrane Transporters ◽

Site Directed Mutagenesis ◽

General Applicability ◽

Regulatory Domains ◽

Acid Transporter ◽

Function Relationship ◽

Basic Features

The localization of membrane transporters at the forefront of natural barriers makes these proteins very interesting due to their involvement in the absorption and distribution of nutrients and xenobiotics, including drugs. Over the years, structure/function relationship studies have been performed employing several strategies, including chemical modification of exposed amino acid residues. These approaches are very meaningful when applied to membrane transporters, given that these proteins are characterized by both hydrophobic and hydrophilic domains with a different degree of accessibility to employed chemicals. Besides basic features, the chemical targeting approaches can disclose information useful for pharmacological applications as well. An eminent example of this picture is the histidine/large amino acid transporter SLC7A5, known as LAT1 (Large Amino Acid Transporter 1). This protein is crucial in cell life because it is responsible for mediating the absorption and distribution of essential amino acids in peculiar body districts, such as the blood brain barrier and placenta. Furthermore, LAT1 can recognize a large variety of molecules of pharmacological interest and is also considered a hot target for drugs due to its over-expression in virtually all human cancers. Therefore, it is not surprising that the chemical targeting approach, coupled with bioinformatics, site-directed mutagenesis and transport assays, proved fundamental in describing features of LAT1 such as the substrate binding site, regulatory domains and interactions with drugs that will be discussed in this review. The results on LAT1 can be considered to have general applicability to other transporters linked with human diseases.

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Aging differentially affects human skeletal muscle amino acid transporter expression when essential amino acids are ingested after exercise

Clinical Nutrition ◽

10.1016/j.clnu.2012.07.009 ◽

2013 ◽

Vol 32 (2) ◽

pp. 273-280 ◽

Cited By ~ 45

Author(s):

Jared M. Dickinson ◽

Micah J. Drummond ◽

Jennifer R. Coben ◽

Elena Volpi ◽

Blake B. Rasmussen

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Amino Acid ◽

Human Skeletal Muscle ◽

Essential Amino Acids ◽

Amino Acid Transporter ◽

Acid Transporter ◽

Transporter Expression

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The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms19082373 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2373 ◽

Cited By ~ 24

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.

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Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00603.2011 ◽

2012 ◽

Vol 302 (9) ◽

pp. E1113-E1122 ◽

Cited By ~ 120

Author(s):

Micah J. Drummond ◽

Jared M. Dickinson ◽

Christopher S. Fry ◽

Dillon K. Walker ◽

David M. Gundermann ◽

...

Keyword(s):

Older Adults ◽

Amino Acid ◽

Protein Content ◽

Bed Rest ◽

Essential Amino Acids ◽

Amino Acid Transporter ◽

Transporter Protein ◽

Mtorc1 Signaling ◽

Acid Transporter ◽

Transporter Expression

Skeletal muscle atrophy during bed rest is attributed, at least in part, to slower basal muscle protein synthesis (MPS). Essential amino acids (EAA) stimulate mammalian target of rapamycin (mTORC1) signaling, amino acid transporter expression, and MPS and are necessary for muscle mass maintenance, but there are no data on the effect of inactivity on this anabolic mechanism. We hypothesized that bed rest decreases muscle mass in older adults by blunting the EAA stimulation of MPS through reduced mTORC1 signaling and amino acid transporter expression in older adults. Six healthy older adults (67 ± 2 yr) participated in a 7-day bed rest study. We used stable isotope tracers, Western blotting, and real-time qPCR to determine the effect of bed rest on MPS, muscle mTORC1 signaling, and amino acid transporter expression and content in the postabsorptive state and after acute EAA ingestion. Bed rest decreased leg lean mass by ∼4% ( P < 0.05) and increased postabsorptive mTOR protein ( P < 0.05) levels while postabsorptive MPS was unchanged ( P > 0.05). Before bed rest acute EAA ingestion increased MPS, mTOR (Ser2448), S6 kinase 1 (Thr389, Thr421/Ser424), and ribosomal protein S6 (Ser240/244) phosphorylation, activating transcription factor 4, L-type amino acid transporter 1 and sodium-coupled amino acid transporter 2 protein content ( P < 0.05). However, bed rest blunted the EAA-induced increase in MPS, mTORC1 signaling, and amino acid transporter protein content. We conclude that bed rest in older adults significantly attenuated the EAA-induced increase in MPS with a mechanism involving reduced mTORC1 signaling and amino acid transporter protein content. Together, our data suggest that a blunted EAA stimulation of MPS may contribute to muscle loss with inactivity in older persons.

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