LAT1 acts as a crucial transporter of amino acids in human thymic carcinoma cells

Hayashi, Keitaro; Jutabha, Promsuk; Maeda, Shin; Yothaisong, Supak; Ouchi, Motoshi; Endou, Hitoshi; Fujita, Tomoe; Chida, Masayuki; Anzai, Naohiko

doi:10.1016/j.jphs.2016.07.006

Cited by 29 publications

(26 citation statements)

References 10 publications

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“…A recent in vitro study noted the possibility of LAT1 molecular targeted therapy for thymic carcinoma patients; namely, we demonstrated that a specific inhibitor of LAT1 had an anti-proliferative effect toward thymic carcinoma cells induced by apoptosis and G1 arrest (Hayashi et al 2016). Based on the present findings of LAT1 expression in thymic carcinomas, anti-LAT1 therapy may be promising as treatment for thymic carcinoma.…”

Section: Discussionsupporting

confidence: 74%

L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma

Maeda

Nakazato

Hayashi

et al. 2018

Tohoku J. Exp. Med.

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L-type amino acid transporter 1 (LAT1) functions to transport large neutral amino acids, such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, and histidine. These amino acids are essential for cell growth and proliferation. Many studies have demonstrated LAT1 expression in various types of cancer, and its high expression level was associated with poor prognosis. However, the significance of LAT1 expression in thymic epithelial tumors is controversial. We conducted this retrospective study to investigate the LAT1 immunoreactivity in thymic epithelial tumors and its impact on prognosis. We analyzed 32 patients with thymoma and 14 patients with thymic carcinoma who underwent surgery at our institute. Immunohistochemical analysis was performed using formalin-fixed paraffinembedded surgical tissues and an anti-LAT1 polyclonal antibody. We thus found that LAT1 immunoreactivity was undetectable in all of the thymoma specimens, regardless of the subtypes of thymoma. By contrast, LAT1 immunoreactivity was consistently detected in the cytosol of thymic carcinoma cells; namely, all 14 thymic carcinoma specimens demonstrated LAT1 immunoreactivity in the cytosol. Among these 14 thymic carcinoma specimens, four carcinoma specimens also showed LAT1 immunoreactivity in the cell membrane. Survival analysis indicated that the thymic carcinoma with the LAT1 membrane signal was associated with poor prognosis, compared with the specimens with the LAT1 cytosol signal. We therefore propose that LAT1 is expressed in the cytosol of thymic carcinoma cells, which could be a diagnostic marker of thymic carcinoma. Moreover, LAT1 expression in the cell membrane is a prognostic marker of thymic carcinoma.

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Section: Discussionsupporting

confidence: 74%

L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma

Maeda

Nakazato

Hayashi

et al. 2018

Tohoku J. Exp. Med.

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“…The molecular mechanism of action of JPH203, investigated using osteosarcoma cell line (Choi et al, 2017 ), consists in activating the mitochondrial pro-apoptotic pathway. This inhibitor is effective also in different type of cancers (Rosilio et al, 2015 ; Hayashi et al, 2016 ; Choi et al, 2017 ; Otsuki et al, 2017 ; Yothaisong et al, 2017 ). Moreover, a synergistic effect with metformin is observed in a cell line of HNC (Head and Neck Cancer) in vitro and in mouse-transplanted model (Ueno et al, 2016 ).…”

Section: Lat1 Druggability and Clinical Outcomesmentioning

confidence: 99%

The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

et al. 2018

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SLC7A5, known as LAT1, belongs to the APC superfamily and forms a heterodimeric amino acid transporter interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide. The complex is responsible for uptake of essential amino acids in crucial body districts such as placenta and blood brain barrier. LAT1/CD98 heterodimer has been studied over the years to unravel the transport mechanism and the role of each subunit. Studies conducted in intact cells demonstrated that LAT1/CD98 mediates a Na+ and pH independent antiport of amino acids. Some novel insights into the function of LAT1 derived from studies conducted in proteoliposomes reconstituted with the recombinant human LAT1. Using this experimental tool, it has been demonstrated that the preferred substrate is histidine and that CD98 is not required for transport being, plausibly, involved in routing LAT1 to the plasma membrane. Since a 3D structure of LAT1 is not available, homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. Over the years, the interest around LAT1 increased because this transporter is involved in important human diseases such as neurological disorders and cancer. Therefore, LAT1 became an important pharmacological target together with other nutrient membrane transporters. Moving from knowledge on structure/function relationships, two cysteine residues, lying on the substrate binding site, have been exploited for designing thiol reacting covalent inhibitors. Some lead compounds have been characterized whose efficacy has been tested in a cancer cell line.

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“…JPH203 is a tyrosine analogue that was designed based on the structure of the thyroid hormone triiodothyronine (T3), which is a substrate of LAT1 and LAT2 [108,109]. JPH203 was subsequently tested in other cancer types and successfully reduced growth of brain [71], gastric [80], head and neck [86], leukemia [50], lung [78], kidney [78], prostate [95], thymic carcinoma [96], and thyroid cancer [59] cell lines. Importantly, LAT1 inhibition by JPH203 has demonstrated a convincing potential in vivo as shown by a diminished tumor growth in xenograft models of human leukemia cells [50] and colon cancer cells [79].…”

Section: Drug-mediated Inhibition Of Lat1mentioning

confidence: 99%

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

Häfliger

Charles

2019

IJMS

143

117

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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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LAT1 acts as a crucial transporter of amino acids in human thymic carcinoma cells

Cited by 29 publications

References 10 publications

L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma

L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma

The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

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

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