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  • br Siqi Du Yadi Wang Nagham Alatrash Choyce A Weatherly


    Siqi Du, Yadi Wang, Nagham Alatrash, Choyce A. Weatherly, Daipayan Roy, Frederick M. MacDonnell, Daniel W. Armstrong ∗ Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019, United States
    Article history:
    Breast cancer
    l- and d-amino acids
    NMDA receptor
    Exchange currency
    Malignancy indicator 
    Herein we describe for the first time the endogenous levels of free l-and d-amino acids in cultured human breast cancer cells (MCF-7) and non-tumorigenic human breast epithelial cells (MCF-10A). d-Asp and d-Ser, which are co-agonists of the N-methyl-d-aspartate (NMDA) receptors, showed significantly elevated levels in MCF-7 cancer cells compared to MCF-10A cells. This may result from upregulated enzymatic racemases. Possible roles of these d-amino acids in promoting breast cancer proliferation by regulating NMDA receptors were indicated. d-Asn may also be able to serve as exchange currency, like specific l-amino acids, for the required uptake of essential amino acids and other low abundance nonessential amino acids which were elevated nearly 60 fold in cancer cells. The relative levels of specific ABT-888 l- and d-amino acids can be used as malignancy indicators (MIs) for the breast cancer cell line in this study. High MIs (>50) result from the increased demands of specific essential amino acids. Very low MIs (<1) result from the increased demands of specific d-amino acids (i.e., d-Ser, d-Asp) or the cellular release of amino ABT-888 exchange currency (i.e., l- and d-Asn) used in the upregulated amino acid antiporters to promote cancer cell proliferation.
    1. Introduction
    Cancer is not a single disease, but a group of related diseases and the most fundamental feature of all cancers is uncontrolled pro-liferation [1]. More than 90 years ago, German physiologist Otto Warburg observed that cancer cells consumed large amounts of glucose compared to normal cells even in the presence of oxygen, which is now known as the Warburg effect [2]. Besides glucose, another principle nutrient supporting the optimal growth of can-cer cells is l-glutamine, as first described by Eagle in the 1950s [3]. While many studies have focused on the metabolism of glucose and l-glutamine in cancer, amino acids besides glutamine also are utilized by cancer cells and may play essential roles in cancer cell proliferation. Recently it has been found that N-methyl-d-aspartate (NMDA) receptors that are widely present in the central nervous
    Abbreviations: NMDA, N-methyl-d-aspartate; CNS, central nervous system; MI, malignancy indicator. ∗ Corresponding author.
    E-mail address: [email protected] (D.W. Armstrong).
    system (CNS) are not only expressed but functional in a variety of cancer cell lines and tumors, e.g., lung cancer, breast cancer, and esophageal cancer, with functions in regulating cancer cell growth and division [4]. It is known that d-Ser, as well as d-Asp and d-Ala, act as co-agonists of NMDA receptors [5–7]. This means d-amino acids, which were once thought to be unnatural and superfluous in mammalian systems [8–11], may play important roles in the metabolism and proliferation of cancer cells. Also, it has been noted in a recent report that non-glutamine amino acids provide abun-dant nitrogen and carbon for biosynthesis to proliferating cells, while most glucose is converted into lactate and exported from can-cer cells [12]. The metabolism and essential roles of many amino acids during cancer cell proliferation may be underestimated or have yet to be considered. Cancer patients are always in a hyper-metabolic state, thus enhanced protein synthesis and degradation can result in the altered amino acid concentrations [13]. Indeed, it is well established that specific amino acid transporters are upregu-lated in cancer cells [14]. Free plasma amino acid profiles in patients with different types of cancer have been found to differ signifi-cantly from those of healthy controls, and the altered amino acid