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: 5.01). 08/2006; 119(3):484-92. DOI: 10.1002/ijc.21866
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Hiroshi Nawashiro, Apr 03, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 4.82 Impact Factor
  • Source
    • "only for protein synthesis but also for the stimulation of cancer cell growth via mammalian targeting of rapamycin (Fuchs and Bode, 2006). Although LAT1 has been described to have a crucial role in the pathogenesis of human neoplasms, the clinical significance of LAT1 expression in pancreatic cancer remains unclear (Fuchs and Bode, 2006; Nawashiro et al, 2006; Nakanishi et al, 2007; Kaira et al, 2008; Sakata et al, 2009; Ichinoe et al, 2011). Previous studies have demonstrated that LAT1 expression is closely associated with CD98, cell proliferation (Ki-67-labelling index), the cell cycle regulator p53 and angiogenesis in patients with thoracic tumours (Kaira et al, 2011a, 2011b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of L-type amino-acid transporter 1 (LAT1) is tumour-specific and has been shown to have essential roles in cell growth and survival. However, little is known regarding the clinical significance of LAT1 expression in pancreatic cancer. This study was conducted to determine the prognostic significance of LAT1 expression. A total of 97 consecutive patients with surgically resected pathological stage I-IV pancreatic ductal adenocarcinoma were retrospectively reviewed. Tumour sections were stained by immunohistochemistry for LAT1, CD98, Ki-67 and vascular endothelial growth factor (VEGF), and microvessel density was determined by CD34 and p53. L-type amino-acid transporter 1 and CD98 were highly expressed in 52.6% (51/97) and 56.7% (55/97) of cases, respectively (P=0.568). The expression of LAT1 within pancreatic cancer cells was significantly associated with disease stage, tumour size, Ki-67, VEGF, CD34, p53 and CD98. L-type amino-acid transporter 1 expression was confirmed to be a significant prognostic factor for predicting poor outcome by multivariate analysis. L-type amino-acid transporter 1 expression is a promising pathological marker for the prediction of outcome in patients with pancreatic cancer.
    British Journal of Cancer 07/2012; 107(4):632-8. DOI:10.1038/bjc.2012.310 · 4.82 Impact Factor
  • Source
    • "SLC7A5 is overexpressed in many cancer types, including SCLC, and its expression levels are usually correlated to cancer progression and aggressiveness [14] [15] [16]. We demonstrated that in SCLC cells, similarly to other tumor types [17] [18] [19], suppression of SLC7A5 expression has an anti-proliferative effect. SCL7A5 suppression or miR-126 overexpression both delay SCLC cells in the G1 phase, suggesting that the effect of miR-126 on the cell cycle is at least in part mediated through SLC7A5. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite intensive efforts to improve therapies, small cell lung cancer (SCLC) still has a dismal median survival of 18 months. Since miR-126 is under-expressed in the majority of SCLC tumors, we investigated the effect of miR-126 overexpression on the proliferation and cell cycle distribution of H69 cells. Our results demonstrate that miR-126 inhibits proliferation of H69 cells, by delaying the cells in the G1 phase. Short interfering RNA (siRNA) mediated suppression of SLC7A5, a predicted target of mir-126, has the same effect on H69 cells. We also show for the first time that SLC7A5 is a direct target of miR-126.
    FEBS letters 03/2011; 585(8):1191-6. DOI:10.1016/j.febslet.2011.03.039 · 3.34 Impact Factor
Show more