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  • br Fig Intracellular percent D amino acid levels


    Fig. 5. Intracellular percent D-amino Cyclosporin H levels. Intracellular % D-Amino acids in MCF-7 and MCF-10A cells after (A) 24-hours, (B) 48-hours, and (C) 72-hours growth in their associated medium. Red bars represent MCF-7 cells grown in high glucose medium, green bars represent MCF-7 cells grown in normal glucose medium, and white bars represent MCF-10A cells grown in the MEGM. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
    Fig. 6. Extracellular D-amino acid profiles. Percent changes of D-amino acids in the media with MCF-7 cells (red: high glucose medium; green: normal glucose medium) and MCF-10A cells (white: MEGM). Values are shown as percent change of d-amino acid in the medium after 72-h incubation from the uncultured medium, with negative bars indicating cellular consumption and positive bars indicating production.
    cells and growth media. Amino acids are hydrophilic molecules and cannot cross the cell membrane without the aid of amino acid transporters. It has been reported that most of the trans-porters show high stereoselectivity, and only a few transporters have been shown to transport d-amino acids, e.g., LAT1, ASCT1, ASCT2, ATB0,+, and EAAT [27–29]. They have shown selectivity to d-Leu, d-Ser, d-Met, d-Phe, and d-Asp. Cellular release of d-Ser (observed in our study) through the less stereoselective amino acid transporters is likely to be important in regulating extracellular lev-els of d-Ser, which activate NMDA receptors and further affects breast cancer cell proliferation. It has been determined that cancer cells express some amino acid transporters at high levels to satisfy their increased demand for amino acids [14]. Interestingly, all the transporters mentioned above have been shown to be upregulated in cancer cells. This further supports the possibility that altered d-amino acid profiles may be a metabolic adaptation to breast cancer cell proliferation. Thus, reducing the availability of the potential oncometabolites, d-Asp and d-Ser, to breast cancer cells could be a possible anticancer strategy. Future studies could explore more on the inhibition of the enzymes/pathways that produce d-Asp and d-Ser, and interference with the upregulated amino acid trans-porters in cancer cells that show selectivity for these d-amino acids. Another notable result was that d-Thr, d-Tyr, and d-Ala also were elevated in MCF-7 cells. Although it has been reported that d-Ala can also bind to NMDA receptor, the presence of Ala racemases have not been confirmed in mammals. Concerning d-Thr and d-Tyr, there are no studies concerning their presence and functions for breast cancer cells to our knowledge. Our results suggest that it may be worthy of exploring the roles of d-Thr, d-Tyr, and d-Ala during cancer cell proliferation.
    3.3. l-Asn and d-Asn may both serve as exchange currency during breast cancer cell proliferation
    Amino acid transporters carry out not only net transport of amino acids (i.e., symporters, substrates travel in the same direc-tion), but also obligatory amino acid exchange (i.e., antiporters), which means uptake of one amino acid via this transporter is obli-gatorily coupled to the export of another amino acid [29]. A recent study indicated that depletion of intracellular and/or extracellular l-Asn in breast cancer cells impaired the uptake of extracellular amino acids, especially l-Ser, l-Arg, and l-His, and reduced cancer cell proliferation [30]. However, the function of d-Asn for cancer cell proliferation was not investigated. In the present study, cel-lular uptake of l-Ser, l-Arg, and l-His was observed for MCF-7 breast cancer cells (Fig. 3). In addition, cellular release of both l-Asn and d-Asn was observed for MCF-7 breast cancer cells, but not for MCF-10A cells (Figs. 3 and 6). Our results support and further sug-gest that intracellular l-Asn, together with d-Asn, exchanges with extracellular amino acids, especially l-Ser, l-Arg, and l-His, to pro-mote cancer cell proliferation [30]. Asn, l- and d-enantiomers, may serve as exchange currency for the uptake of essential amino acids and/or low abundance nonessential amino acids that are required by cancer cells during proliferation.