Inhibition of L-Type Amino Acid Transporter Modulates the Expression of Cell Cycle Regulatory Factors in KB Oral Cancer Cells

Abstract

Amino acid transport system L is a cell membrane protein that transports neutral amino acid and known to be the major route of neutral amino acids for cell proliferation.1-3) Kanai et al. identified the first isoform of amino acid transport system L (L-type amino acid transporter 1, LAT1) from C6 glioma cells.4) It is predicted to be 12-membrane-spanning proteins, and mediates Na ϩ -independent amino acid exchange and prefers large neutral amino acids with bulky or branched side chains for its substrates. [4][5][6][7][8] Following the molecular identification of LAT1, the second isoform of amino acid transport system L (L-type amino acid transporter 2, LAT2) has been identified. [9][10][11] It has the characteristics of transporting small neutral amino acids as well as large neutral amino acids. [10][11][12] LAT1 is only expressed in restricted organs such as brain, spleen, placenta and testis. 4,13) However, LAT2 is more ubiquitously expressed than LAT1. [10][11][12] Importantly, LAT1 is highly expressed in malignant tumors presumably to support their continuous growth and proliferation. 4,5,14,15) Based on the characteristics of LAT1 and LAT2, it is proposed that the manipulation of system L activity, particularly that of LAT1, would have therapeutic implications for cancer treatment. If the activity of LAT1 should be suppressed and thereby the depletion of intracellular neutral amino acids should be induced, this would be helpful for inducing the inhibition of cancer cell growth. However, the mechanism by which inhibition of LAT1 can cause cancer cell growth suppression or cytotoxicity of cancer cells is not entirely clear.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. [4][5][6]11,16,17) Substrates for amino acid transport system L include several essential amino acids such as leucine, isoleucine, valine, phenylalanine, methionine and histidine.1-3) Therefore, the suppression of L-type amino transpoter activity using BCH could be effective in the retardation of tumor cell growth by depleting the intracellular essential amino acids. In this study, we attempted to clarify the effect of BCH on the expression of factors regulating the cell cycle to cause cell cycle arrest in KB human oral cancer cells. We report here that the BCH arrests KB cell growth at G1 phase of cell cycle through the inhibition of cyclin D3-cyclin-dependent protein kinase 6 (CDK6) complex expression while increasing the expression of p27, a CDK inhibitor. Cell Cultures KB cells were grown in Dulbecco's modi- The purpose of this study was to examine the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of L-type amino acid transporters, on the cell growth suppression in KB human oral cancer cells and to study the roles of cell cycle regulatory factors in the BCH-induced growth inhibition. The effect of BCH on cell growth suppression and the influence of BCH to cell cycle regulatory factors in KB cell gro...

JPH203, an L-Type Amino Acid Transporter 1–Selective Compound, Induces Apoptosis of YD-38 Human Oral Cancer Cells

“…Based on the characteristics of LAT1 and LAT2, it is proposed that the manipulation of the system L activity, particularly that of LAT1 as a molecular target for cancer therapy, would have therapeutic implications in cancer treatment (18). Suppressing the activity of LAT1, thereby depleting the intracellular neutral amino acids, would be helpful for inducing the inhibition of cancer cell growth (18).…”

“…Suppressing the activity of LAT1, thereby depleting the intracellular neutral amino acids, would be helpful for inducing the inhibition of cancer cell growth (18). When the LAT1-selective activity in tumor cells becomes blocked completely, normal cell growth and proliferation would presumably still be possible due to the presence of LAT2 (18).…”

Antitumor activity of an anti‐CD98 antibody

“…Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus. 5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we used in vivo phenotypic screening.…”

Canine Lat1: Molecular Structure, Distribution and Its Expression in Cancer Samples

“…Among them, Lat1 drew special attention because cancer cells possessed potent Lat1 expression, whereas normal cells did not [18,22]. Additionally, it has been demonstrated that the inhibition of Lat1 expression exerts an inhibitory effect on cancer growth [10,11,14].…”