Roles of N-methyl-d-aspartate receptors and d-amino acids in cancer cell viability

Du, Shoucheng; Sung, Yu-Sheng; Wey, Michael; Wang, Yadi; Alatrash, Nagham; Berthod, Alain; MacDonnell, Frederick M.; Armstrong, Daniel W.

doi:10.1007/s11033-020-05733-8

Cited by 18 publications

(15 citation statements)

References 43 publications

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“…A highly significant observation is that a subset of cells showed higher levels of Glutamate, GABA, or 5-HT ( Figure 6 ). GABA, Glu, and 5-HT have been well characterized as neurotransmitters as well as neurotrophic factors that activate intracellular signaling pathway via the stimulation of specific sets of cell surface receptors [ 23 , 24 , 25 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. Evidence is emerging that they can elicit diverse non-neuronal response by stimulating their receptors in non-neuronal tissues and recent studies have shown that the extra-neuronal synthesis and release of neurotransmitters cells into the TME by the cancer cells promote tumorigenesis and tumor progression in many cancers [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Evidence is emerging that they can elicit diverse non-neuronal response by stimulating their receptors in non-neuronal tissues and recent studies have shown that the extra-neuronal synthesis and release of neurotransmitters cells into the TME by the cancer cells promote tumorigenesis and tumor progression in many cancers [ 23 ]. While these transmitters have been shown to stimulate cell proliferation in different cancers [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ], identification of them as potential oncometabolites or their role as mediators of autocrine signaling in ovarian cancer is hitherto unreported. Our results, presented here indicate that the antagonists of these metabolism-derived ligands can effectively disrupt the autocrine signaling loop and inhibit ovarian cancer cell proliferation ( Figure 7 , Figure 8 , Figure 9 , Figure 10 and Figure 11 ).…”

Section: Discussionmentioning

confidence: 99%

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Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

Jayaraman

Nadhan

et al. 2021

Biomedicines

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Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established the heterogeneity of the HGSOC cells by clustering them into five distinct metabolic groups compared to the fallopian tube epithelial cell line control. An overall increase in the metabolites associated with aerobic glycolysis and phospholipid metabolism were observed in the majority of the cancer cells. A preponderant increase in the levels of metabolites involved in trans-sulphuration and glutathione synthesis was also observed. More significantly, subsets of HGSOC cells showed an increase in the levels of 5-Hydroxytryptamine, γ-aminobutyrate, or glutamate. Additionally, 5-hydroxytryptamin synthesis inhibitor as well as antagonists of γ-aminobutyrate and glutamate receptors prohibited the proliferation of HGSOC cells, pointing to their potential roles as oncometabolites and ligands for receptor-mediated autocrine signaling in cancer cells. Consistent with this role, 5-Hydroxytryptamine synthesis inhibitor as well as receptor antagonists of γ-aminobutyrate and Glutamate-receptors inhibited the proliferation of HGSOC cells. These antagonists also inhibited the three-dimensional spheroid growth of TYKNU cells, a representative HGSOC cell-line. These results identify 5-HT, GABA, and Glutamate as putative oncometabolites in ovarian cancer metabolic sub-type and point to them as therapeutic targets in a metabolomic fingerprinting-based therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

Jayaraman

Nadhan

et al. 2021

Biomedicines

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“…Notably, the growth of human prostate, breast, and pancreatic cancer cells was halted when NMDA receptor activity was blocked by channel blockers, such as dizocilpine (MK-801) and memantine [ 81 , 82 , 83 ]. The same molecules inhibited the growth of human skin cells by reducing or stopping NMDA receptor activity [ 84 ]. The antiproliferative effect due to MK-801 or memantine addition was reversed by D-Ser, D-Ala, or D-Asp administration ( Figure 2 ).…”

Section: Proposed Roles Of D-amino Acids In Cancermentioning

confidence: 99%

“…This evidence suggests a possible innovative anticancer therapy based on reducing the availability of D-Asp and D-Ser for breast cancer cells and/or acting on the D-AAs metabolic pathways, i.e., on the enzymes related to their synthesis and degradation. Intriguingly, as the growth medium did not contain D-AAs, their endogenous production implicates the presence of undiscovered synthetic systems in skin cancer cells [ 84 ].…”

Section: Proposed Roles Of D-amino Acids In Cancermentioning

confidence: 99%

D-Amino Acids and Cancer: Friends or Foes?

Murtas

Pollegioni

2023

IJMS

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α-amino acids exist in two configurations, named D-(dextro) and L-(levo) enantiomers. L-amino acids are used in protein synthesis and play a central role in cell metabolism. The effects of the L-amino acid composition of foods and the dietary modifications of this composition on the efficacy of cancer therapies have been widely investigated in relation to the growth and reproduction of cancerous cells. However, less is known about the involvement of D-amino acids. In recent decades, D-amino acids have been identified as natural biomolecules that play interesting and specific roles as common components of the human diet. Here, we focus on recent investigations showing altered D-amino acid levels in specific cancer types and on the various roles proposed for these biomolecules related to cancer cell proliferation, cell protection during therapy, and as putative, innovative biomarkers. Notwithstanding recent progress, the relationship between the presence of D-amino acids, their nutritional value, and cancer cell proliferation and survival represents an underrated scientific issue. Few studies on human samples have been reported to date, suggesting a need for routine analysis of D-amino acid content and an evaluation of the enzymes involved in regulating their levels in clinical samples in the near future.

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“…For example, in the brain of mammals, d -serine has important biological effects in N -methyl- d -aspartate-type glutamate receptors. In addition, d -AA-containing peptides are found to exhibit physiological importance and are associated with neurological disorders. − Stereospecific and enantiomeric purity analysis should contribute to discover abnormal alteration of endogenous chiral metabolites and promote the development of protein sequencing and pharmaceutical investigation. , …”

Section: Introductionmentioning

confidence: 99%

Powerful Steroid-Based Chiral Selector for High-Throughput Enantiomeric Separation of α-Amino Acids Utilizing Ion Mobility–Mass Spectrometry

Zhou

Wang

et al. 2021

Anal. Chem.

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Stereospecific recognition of amino acids (AAs) plays a crucial role in chiral biomarker-based diagnosis and prognosis. Separation of AA enantiomers is a long and tedious task due to the requirement of AA derivatization prior to the chromatographic or electrophoretic steps which are also timeconsuming. Here, a mass-tagged chiral selector namedhigh reactivity and good enantiomeric resolution in regard to AAs was developed. After a quick and easy chemical derivatization step of AAs using 17β-EBC as the single chiral selector before ion mobility−mass spectrometry analysis, good enantiomer separation was achieved for 19 chiral proteinogenic AAs in a single analytical run (∼2 s). A linear calibration curve of enantiomeric excess was also established using [d 0 ]/[d 5 ]-17β-EBC. It was demonstrated to be capable of determining enantiomeric ratios down to 0.5% in the nanomolar range. 17β-EBC was successfully applied to investigate the absolute configuration of AAs among peptide drugs and detect trace levels of D-AAs in complex biological samples. These results indicated that [d 0 ]/[d 5 ]-17β-EBC may contribute to entail a valuable step forward in peptide drug quality control and discovering chiral disease biomarkers.

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Roles of N-methyl-d-aspartate receptors and d-amino acids in cancer cell viability

Cited by 18 publications

References 43 publications

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

D-Amino Acids and Cancer: Friends or Foes?

Powerful Steroid-Based Chiral Selector for High-Throughput Enantiomeric Separation of α-Amino Acids Utilizing Ion Mobility–Mass Spectrometry

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