title: Steroid hormones are novel nucleoside transport inhibitors by competition with nucleosides for their transporters.
abstract: Nucleoside transport is important for nucleic acid synthesis in cells that cannot synthesize nucleosides de novo, and for entry of many cytotoxic nucleoside analog drugs used in chemotherapy. This study demonstrates that various steroid hormones induce inhibition of nucleoside transport in mammalian cells. We analyzed the inhibitory effects of estradiol (E2) on nucleoside transport using SH-SY5Y human neuroblastoma cells. We observed inhibitory effects after acute treatment with E2, which lasted in the presence of E2. However, when E2 was removed, the effect immediately disappeared, suggesting that E2 effects are not mediated through the canonical regulatory pathway of steroid hormones, such as transcriptional regulation. We also discovered that E2 could competitively inhibit thymidine uptake and binding of the labeled nucleoside transporter inhibitor, S-[4-nitrobenzyl]-6-thioinosine (NBTI), indicating that E2 binds to endogenous nucleoside transporters, leading to inhibition of nucleoside transport. We then tested the effects of various steroids on nucleoside uptake in NBTI-sensitive cells, SH-SY5Y and NBTI-insensitive cells H9c2 rat cardiomyoblasts. We found E2 and progesterone clearly inhibited both NBTI-sensitive and insensitive uptake at micromolar concentrations. Taken together, we concluded that steroid hormones function as novel nucleoside transport inhibitors by competition with nucleosides for their transporters.
authors: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.
authors: Masahiro
authors: M
authors: Kaneko
authors: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.
authors: Fumihiko
authors: F
authors: Hakuno
authors: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.
authors: Hiroyasu
authors: H
authors: Kamei
authors: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan; Department of Bioregulation, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan.
authors: Daisuke
authors: D
authors: Yamanaka
authors: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.
authors: Kazuhiro
authors: K
authors: Chida
authors: Department of Bioregulation, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan.
authors: Shiro
authors: S
authors: Minami
authors: Faculty of Science, Ryerson University, 350 Victoria St., Toronto, ON M5B 2K3, Canada.
authors: Imogen R
authors: IR
authors: Coe
authors: Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan. Electronic address: atkshin@mail.ecc.u-tokyo.ac.jp.
authors: Shin-Ichiro
authors: S
authors: Takahashi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage*; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism*; D011374:Progesterone / Q000008:administration & dosage*; D051381:Rats
chemical_list: D012739:Gonadal Steroid Hormones; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D011374:Progesterone; D004958:Estradiol
keywords: BSA; CNT; DMEM; Dulbecco’s modified Eagle’s medium; E2; EDTA; ENT; Estradiol; FBS; NBTI; NBTI (S-[4-nitrobenzyl]-6-thioinosine); NT; Nucleoside transporter; P4; PBS; S-[4-nitrobenzyl]-6-thioinosine; Steroid hormone; bovine serum albumin; concentrative nucleoside transporter; equilibrative nucleoside transporter; estradiol; ethylenediaminetetraacetic acid; fetal bovine serum; nucleoside transporter; phosphate buffered serine; progesterone