L-Type amino acid transporter 1 as a potential molecular target in human astrocytic tumors

Department of Neurosurgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
International Journal of Cancer (Impact Factor: 5.09). 08/2006; 119(3):484-92. DOI: 10.1002/ijc.21866
Source: PubMed


L-type amino acid transporter 1 (LAT1) is a Na+-independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunohistochemistry. Kaplan-Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p<0.0001) and for those with glioblastoma multiforme in particular (p=0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2-aminobicyclo-2 (2,2,1)-heptane-2-carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose-dependent manner. Kaplan-Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy.

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Available from: Hiroshi Nawashiro, Apr 03, 2015
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    • "Recent studies have focussed on ASCT2 and LAT1, which are highly expressed in cancer cells (Fuchs and Bode, 2006). The overexpression of LAT1 may be a significant predictor of poor prognosis, and it is closely linked to the aggressiveness and metastasis of various human neoplasms (Nawashiro et al, 2006; Nakanishi et al, 2007; Kaira et al, 2008, 2012; Sakata et al, 2009; Ichinoe et al, 2011; Furuya et al; 2012). "
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    ABSTRACT: Background: ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear. Methods: One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort. Results: ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients. Conclusions: ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.
    British Journal of Cancer 03/2014; 110(8). DOI:10.1038/bjc.2014.88 · 4.84 Impact Factor
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    • "LAT1 was the first LAT isoform to be isolated, and it has been reported that LAT1 is overexpressed in primary human neoplasms and involved in tumor cell proliferation due to its role in the transport of essential amino acids [10,33]. There is evidence that increased LAT1 expression is associated with a poor prognosis of various cancers, including brain tumors [11], lung cancer [12], gastric cancer [13], urothelial cancer [14], and prostatic cancer [15]. Furthermore, it has been reported that LAT1 not only provides cancer cells with amino acids required for protein synthesis but also with amino acids that stimulate cell growth via mammalian targeting of rapamycin (mTOR) [31], and that the amino acid supply is coupled to cell signaling via mTOR in mammalian cells and influences both cell growth and cell cycle progression [34,35]. "
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    ABSTRACT: The system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer. To clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real-time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting. Expression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors. These findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC.
    BMC Cancer 10/2013; 13(1):509. DOI:10.1186/1471-2407-13-509 · 3.36 Impact Factor
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    • "Tsukahara et al. showed that the novel anticancer chemical E7070 inhibits leucine and uracil transporters in the fission yeast, Schizosaccharomyces pombe, and may also target mammalian transporters [42]. It has also been reported that inhibitors of the mammalian amino acid permease, LAT1, that preferentially transports branched-chain and aromatic amino acids through the plasma membrane, may be an effective therapeutic option for human astrocytic tumors [43]. Based on these considerations, amino acid permease inhibitors such as eugenol may hold chemotherapeutic promise for human cancers. "
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    ABSTRACT: Eugenol is an aromatic component of clove oil that has therapeutic potential as an antifungal drug, although its mode of action and precise cellular target(s) remain ambiguous. To address this knowledge gap, a chemical-genetic profile analysis of eugenol was done using ∼4700 haploid Saccharomyces cerevisiae gene deletion mutants to reveal 21 deletion mutants with the greatest degree of susceptibility. Cellular roles of deleted genes in the most susceptible mutants indicate that the main targets for eugenol include pathways involved in biosynthesis and transport of aromatic and branched-chain amino acids. Follow-up analyses showed inhibitory effects of eugenol on amino acid permeases in the yeast cytoplasmic membrane. Furthermore, phenotypic suppression analysis revealed that eugenol interferes with two permeases, Tat1p and Gap1p, which are both involved in dual transport of aromatic and branched-chain amino acids through the yeast cytoplasmic membrane. Perturbation of cytoplasmic permeases represents a novel antifungal target and may explain previous observations that exposure to eugenol results in leakage of cell contents. Eugenol exposure may also contribute to amino acid starvation and thus holds promise as an anticancer therapeutic drug. Finally, this study provides further evidence of the usefulness of the yeast Gene Deletion Array approach in uncovering the mode of action of natural health products.
    PLoS ONE 10/2013; 8(10):e76028. DOI:10.1371/journal.pone.0076028 · 3.23 Impact Factor
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