title: 2-methoxyestradiol impacts on amino acids-mediated metabolic reprogramming in osteosarcoma cells by its interaction with NMDA receptor.
abstract: Deregulation of serine and glycine metabolism, have been identified to function as metabolic regulators in supporting tumor cell growth. The role of serine and glycine in regulation of cancer cell proliferation is complicated, dependent on concentrations of amino acids and tissue-specific. D-serine and glycine are coagonists of N-methyl-D-aspartate (NMDA) receptor subunit GRIN1. Importantly, NMDA receptors are widely expressed in cancer cells and play an important role in regulation of cell death, proliferation, and metabolism of numerous malignancies. The aim of the present work was to associate the metabolism of glycine and D-serine with the anticancer activity of 2-methoxyestradiol. 2-methoxyestradiol is a potent anticancer agent but also a physiological 17β- estradiol metabolite. In the study we have chosen two malignant cell lines expressing functional NMDA receptors, that is osteosarcoma 143B and breast cancer MCF7. We used MTS assay, migration assay, flow cytometric analyses, Western blotting and immunoprecipitation techniques as well as molecular modeling studies. We have demonstrated the extensive crosstalk between the deregulated metabolic network and cancer cell signaling. Herein, we observed an anticancer effect of high concentrations of glycine and D-serine in osteosarcoma cells. In contrast, the amino acids when used at low, physiological concentrations induced the proliferation and migration of osteosarcoma cells. Importantly, the pro-cancergogenic effects of both glycine and D-serine where abrogated by the usage of 2-methoxyestradiol at both physiological and pharmacological relevant concentrations. The obtained data confirmed that 2-methoxyestradiol may be a physiological anticancer molecule.
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Magdalena
authors.identifier: http://orcid.org/0000-0002-7366-8429
authors.initials: M
authors.lastname: Gorska-Ponikowska
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Viale delle Scienze, Edificio 17, Palermo, Italy.|Fondazione Ri.MED, Palermo, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Perricone
authors.affiliation: Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Kuban-Jankowska
authors.affiliation: Dipartimento di Matematica e Informatica, Università degli Studi di Palermo, Palermo, Italy.|Istituto Euro Mediterraneo di Scienza e Tecnologia, Palermo, Italy.
authors.forename: Giosuè
authors.initials: G
authors.lastname: Lo Bosco
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Viale delle Scienze, Edificio 17, Palermo, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Barone
mesh_terms: D000077584:2-Methoxyestradiol; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D000072417:Protein Domains; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012694:Serine / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000077584:2-Methoxyestradiol; D000970:Antineoplastic Agents; D004958:Estradiol; D005998:Glycine; D009419:Nerve Tissue Proteins; D052248:Nitric Oxide Synthase Type I; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D050257:Tubulin Modulators; C485668:GRIN1 protein, human; C496320:NOS1 protein, human
keywords: 2-methoxyestradiol; D-serine; NMDA receptors; glycine; neuronal nitric oxide synthase; osteosarcoma