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Thymidine 5′-O-monophosphorothioate induces HeLa cell migration by activation of the P2Y6 receptor

Significance Statement

Ligands of the P2Y nucleotide receptors are of potential interest for pharmacotherapies directed at neurodegenerative disorders, intestinal function, angiogenesis, cardiac remodeling,  etc.  Activation of P2Y6 by its native ligand UDP or by synthetic agonists is associated with vasoconstriction and cytoprotection. P2Y6 seems to control chloride secretion by epithelium, the direct contraction and endothelium-dependent relaxation of the aorta or insulin secretion as well. Pharmacological modulation of the P2Y6 receptor is of increasing interest, nevertheless UDP as a natural ligand was reported to activate not only P2Y6 but also P2Y14. Therefore, agonists that delineate between these two subtypes are needed. Besides, the therapeutic potential of extracellular nucleotides is limited because they are degraded by extracellular enzymes which reduce their efficacy and duration of action. We pay particular attention to the unique activity of thymidine 5’-O-monophosphorothioate (TMPS) which acts as a specific partial agonist of the P2Y6 receptor. Its  increased stability as compared to their unmodified counterpart as well as their affinity towards P2Y6 is especially interesting and may be responsible for some long-term effects.  

Thymidine 5'-O-monophosphorothioate induces HeLa cell migration by activation of the P2Y6 receptor. Global Medical Discovery

About The Author

Edyta Gendaszewska-Darmach:

PhD degree in Bioorganic Chemistry from Polish Academy of Sciences.

an Asissstant Professor at Faculty of Biotechnology and Food Sciences (Institute of Technical Biochemistry),  Lodz University of Technology.

Research involves anti-diabetic and wound healing properties of natural and modified biophosphates (nucleotides and lysophospholipids) as well as biomaterials for regenerative medicine.

Journal Reference

Purinergic Signal. 2016 Jan 8.

Gendaszewska-Darmach E1, Szustak M2.

Show Affiliations
  1. Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924, Lodz, Poland. [email protected]
  2. Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924, Lodz, Poland.

Abstract

ATP, ADP, UTP, and UDP acting as ligands of specific P2Y receptors activate intracellular signaling cascades to regulate a variety of cellular processes, including proliferation, migration, differentiation, and cell death. Contrary to a widely held opinion, we show here that nucleoside 5′-O-monophosphorothioate analogs, containing a sulfur atom in a place of one nonbridging oxygen atom in a phosphate group, act as ligands for selected P2Y subtypes. We pay particular attention to the unique activity of thymidine 5′-O-monophosphorothioate (TMPS) which acts as a specific partial agonist of the P2Y6 receptor (P2Y6R). We also collected evidence for the involvement of the P2Y6 receptor in human epithelial adenocarcinoma cell line (HeLa) cell migration induced by thymidine 5′-O-  monophosphorothioate analog. The stimulatory effect of TMPS was abolished by siRNA-mediated P2Y6 knockdown and diisothiocyanate derivative MRS 2578, a selective antagonist of the P2Y6R. Our results indicate for the first time that increased stability of thymidine 5′-O-monophosphorothioate as well as its affinity toward the P2Y6R may be responsible for some long-term effects mediated by this receptor.

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