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...