Gendaszewska-Darmach Edyta, Szustak Marcin
Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924, Lodz, Poland.
Purinergic Signal. 2016 Jun;12(2):199-209. doi: 10.1007/s11302-015-9492-1. Epub 2016 Jan 8.
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.
ATP、ADP、UTP和UDP作为特定P2Y受体的配体，激活细胞内信号级联反应，以调节多种细胞过程，包括增殖、迁移、分化和细胞死亡。与广泛持有的观点相反，我们在此表明，核苷5'-O-单磷酸硫代磷酸酯类似物，即在磷酸基团的一个非桥连氧原子位置含有一个硫原子，可作为选定P2Y亚型的配体。我们特别关注胸苷5'-O-单磷酸硫代磷酸酯（TMPS）的独特活性，它作为P2Y6受体（P2Y6R）的特异性部分激动剂。我们还收集了证据，证明P2Y6受体参与了由胸苷5'-O-单磷酸硫代磷酸酯类似物诱导的人上皮腺癌细胞系（HeLa）细胞迁移。TMPS的刺激作用被siRNA介导的P2Y6基因敲低和二异硫氰酸酯衍生物MRS 2578（P2Y6R的选择性拮抗剂）所消除。我们的结果首次表明，胸苷5'-O-单磷酸硫代磷酸酯稳定性的增加及其对P2Y6R的亲和力可能是该受体介导的一些长期效应的原因。
