Roles of N-methyl- d -aspartate receptors and d -amino acids in cancer cell viability
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ORIGINAL ARTICLE
Roles of N‑methyl‑d‑aspartate receptors and d‑amino acids in cancer cell viability Siqi Du1 · Yu‑Sheng Sung1 · Michael Wey1 · Yadi Wang1 · Nagham Alatrash1 · Alain Berthod2 · Frederick M. MacDonnell1 · Daniel W. Armstrong1 Received: 12 June 2020 / Accepted: 19 August 2020 © Springer Nature B.V. 2020
Abstract N-methyl-d-aspartate (NMDA) receptors, which are widely present in the central nervous system, have also been found to be up-regulated in a variety of cancer cells and tumors and they can play active roles in cancer cell growth regulation. NMDA receptor antagonists have been found to affect cancer cell viability and interfere with tumor growth. Moreover, cancer cells also have been shown to have elevated levels of some d-amino acids. Two human skin cell lines: Hs 895.T skin cancer and Hs 895.Sk skin normal cells were investigated. They were derived from the same patient to provide tumor and normal counterparts for comparative studies. The expression of specific NMDA receptors was confirmed for the first time in both skin cell lines. Dizocilpine (MK-801) and memantine, NMDA receptor channel blockers, were found to inhibit the growth of human skin cells by reducing or stopping NMDA receptor activity. Addition of d-Ser, d-Ala, or d-Asp, however, significantly reversed the antiproliferative effect on the human skin cells triggered by MK-801 or memantine. Even more interesting was the finding that the specific intracellular composition of a few relatively uncommon amino acids was selectively elevated in skin cancer cells when exposed to MK-801. It appears that a few specific and upregulated d-amino acids can reverse the drug-induced antiproliferative effect in skin cancer cells via the reactivation of NMDA receptors. This study provides a possible innovative anticancer therapy by acting on the d-amino acid pathway in cancer cells either blocking or activating their regulatory enzymes. Keywords d-amino acids · NMDA receptors · Skin cancer · MK-801 · Memantine · Antiproliferative Abbreviations NMDA receptors N-methyl-d-aspartate receptors MK-801 Dizocilpine CNS Central nervous system Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11033-020-05733-8) contains supplementary material, which is available to authorized users.
DAAO d-amino acid oxidase AD Alzheimer’s disease AQC 6-Aminoquinolyl-N-hydroxysuccinimide carbamate HPLC–MS High performance liquid chromatography-mass spectrometry BCA Bicinchoninic acid
* Daniel W. Armstrong [email protected]
Alain Berthod berthod@univ‑lyon1.fr
Siqi Du [email protected]
Frederick M. MacDonnell [email protected]
Yu‑Sheng Sung yu‑[email protected]
1
Michael Wey [email protected]
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019, USA
2
Institut des Sciences Analytiques, CNRS, Université de Lyon 1, 5 rue de la Doua, 69100 Villeurbanne, France
Yadi Wang [email protected] Nagham Alatrash [email protected]
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