title: Orotate phosphoribosyltransferase localizes to the Golgi complex and its expression levels affect the sensitivity to anti-cancer drug 5-fluorouracil.
abstract: Orotate phosphoribosyltransferase (OPRT) is engaged in de novo pyrimidine synthesis. It catalyzes oronitine to uridine monophosphate (UMP), which is used for RNA synthesis. De novo pyrimidine synthesis has long been known to play an important role in providing DNA/RNA precursors for rapid proliferative activity of cancer cells. Furthermore, chemotherapeutic drug 5-fluorouracil (5-FU) is taken up into cancer cells and is converted to 5-fluoro-UMP (FUMP) by OPRT or to 5-fluoro-dUMP (FdUMP) through intermediary molecules by thymidine phosphorylase. These 5-FU metabolites are misincorporated into DNA/RNA, thereby producing dysfunction of these information processing. However, it remains unclear how the subcellular localization of OPRT and how its variable expression levels affect the response to 5-FU at the cellular level. In this study, immunocytochemical analysis reveals that OPRT localizes to the Golgi complex. Results also show that not only overexpression but also downregulation of OPRT render cells susceptible to 5-FU exposure, but it has no effect on DNA damaging agent doxorubicin. This study provides clues to elucidate the cellular response to 5-FU chemotherapy in relation to the OPRT expression level.
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Hozumi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakano
authors.forename: Hirooki
authors.initials: H
authors.lastname: Matsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Nasu
authors.forename: Shuji
authors.initials: S
authors.lastname: Koike
authors.forename: Seiji
authors.initials: S
authors.lastname: Kakehata
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ito
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004249:DNA Damage / Q000187:drug effects; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil