BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells

Abstract

Amino acids are essential to support protein synthesis, which is required for cell growth and proliferation. Amino acid uptake into the cell is mediated by amino acid transporters located on the plasma membrane. 1,2)The system L amino acid transporters are an amino acid transport system that transports neutral amino acids, including several essential amino acids, in a Na ϩ -independent manner.1,3) It is a major route for providing living cells, including cancer cells, with amino acids. 1,3)We isolated LAT1 (L-type amino acid transporter 1), the first isoform of a system L amino acid transporter, from C6 rat glioma cells.4) Subsequently, we and other researchers cloned LAT2 (L-type amino acid transporter 2), the second isoform of a system L amino acid transporter.5-7) The structure and function of LAT1 are very similar to those of LAT2. Both isoforms are predicted to be 12-membrane-spanning proteins.4-7) They require an additional single-membranespanning protein, the heavy chain of 4F2 antigen (4F2hc), for their functional expression in the plasma membrane. [4][5][6][7][8][9][10][11][12] Both LAT1 and LAT2 form a heterodimeric complex via a disulfide bond with 4F2hc. [4][5][6][7][8][9][10][11][12] However, LAT2 is more ubiquitously expressed than LAT1, and it transports not only large neutral amino acids, but also small neutral amino acids in a fashion that appears to have broader substrate selectivity than LAT1. [4][5][6][7][9][10][11][12][13][14] In addition, LAT1 is highly expressed in malignant tumors, presumably to support their continuous growth and proliferation. 4,8,15,16) 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is a model compound for the study of amino acid transporters, as it is a system L selective inhibitor.1,17) Because system L amino acid transporters transport neutral amino acids, including several essential amino acids, if they are blocked in living cells by a specific inhibitor such as BCH, the cells would be damaged; damage would be caused specifically by the deprivation of amino acids necessary for protein synthesis, cell growth and proliferation. In addition, several reports have demonstrated that amino acid uptake increased during the proliferation process of cancer cells to support DNA and protein biosynthesis. [18][19][20] It is proposed that the manipulation of system L activity, particularly that of LAT1, would have therapeutic implications. The inhibition of LAT1 activity in cancer cells could be effective in the suppression of cancer cell growth by depriving cancer cells of essential amino acids.17,21) However, the mechanism by which inhibition of LAT1 can cause cancer cell growth suppression or cytotoxicity of cancer cells is not entirely clear.In this study, we examined the effect of BCH on cell growth and its mechanism of cell growth suppression in cancer cells. We used cells that highly expressed only LAT1 among all the system L transporters. [22][23][24] Our results show that the system L selective inhibitor BCH, at suitable concentrations, can induce the suppressio...

Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability

“…Although inhibition of LAT1 affects cell proliferation (47,48), its genetic or chemical ablation results in mTOR inhibition and impaired cell growth (27, 28, 48 -50). Our data indicate that Ͼ90% of L-isoleucine uptake is lost when CD98hc is absent.…”

“…By expressing such transporters coupled with extracellular matrix receptors, cells can control AA adequacy, reactive oxygen species impact, and anchoring/migration, leading to sustain cell proliferation, critical for tumor cells (54). To date, many studies have focused on the search for either transporter (xCT, LAT1) inhibitors or integrin antagonists as anti-cancer strategies (47,48,55,56). Even though these molecules are appealing targets, encouraging, yet limited results, have been obtained so far.…”

High Ki67, Bax, and thymidylate synthase expression well correlates with response to chemoradiation therapy in locally advanced rectal cancers: proposal of a logistic model for prediction

“…In addition, L-type amino-acid transporter 1 (LAT1) is highly expressed in malignant tumours to support growth and proliferation, and the inhibition of LAT1 activity led to cancer cell apoptosis (Kim et al, 2008).…”

One-step synthesis of an 18F-labeled boron-derived methionine analog: a substitute for 11C-methionine?

“…Several comparative studies have shown that amino acidbased tracers have better performance than 18 F-FDG in brain tumor diagnosis [2][3][4]. Whereas 18 F-FDG uptake is generally a measure of glucose metabolism, amino acid-based PET can provide information on amino acid metabolism and the function of various amino acid transporters. Currently, amino acidbased PET scans are often performed in the clinic when a brain tumor is diagnosed by either magnetic resonance imaging (MRI) or computed tomography (CT), which can aid in personalized treatment planning.…”

“…However, widespread clinical application of possible due to the short half-life of 11 C (20.38 min) and low efficiency in radiolabeling (radiochemical yield usually <5%). The use of 18 F to label methionine, without interfering with its biological activity, may solve this problem due to the longer half-life of 18 F (109.7 min) and its wide availability at the majority of PET centers. However, direct labeling of methionine with 18 F is very challenging, since even minor modification of the side chain will significantly alter the biological properties of the resulting methionine analog.…”