title: Disrupted plasma membrane localization of equilibrative nucleoside transporter 2 in the chemoresistance of human pancreatic cells to gemcitabine (dFdCyd).
abstract: Although the nucleoside pyrimidine analogue gemcitabine is the most effective single agent in the palliation of advanced pancreatic cancer, cellular resistance to gemcitabine treatment is a major problem in the clinical scene. To clarify the molecular mechanisms responsible for chemoresistance to gemcitabine, mRNA expression of the key enzymes including cytidine deaminase (CDA), deoxycytidine kinase (dCK), 5'-nucleotidase (NT5), equilibrative nucleoside transporter 1 and 2 (ENT1 and ENT2), dCMP deaminase (dCMPK), ribonucleotide reductase M1 and M2 (RRM1 and RRM2), thymidylate synthase (TS) and CTP synthase (CTPS) was examined. The interacellular uptake of gemcitabine was greatly impaired in the chemoresistant cell lines due to dysfunction of ENT1 and ENT2. Protein expression of ENT1 and ENT2 and their protein coding sequences were not altered. Immunohistochemical and western blot analyses revealed that localization of ENT2 on the plasma membrane was disrupted. These data suggest that the disrupted localization of ENT2 is one of causes of the impaired uptake of gemcitabine, resulting in a gain of chemoresistance to gemcitabine.
authors.affiliation: Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Yonago, Japan.
authors.forename: Ren
authors.initials: R
authors.lastname: Nishio
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Yasui
authors.forename: Shizuka
authors.initials: S
authors.lastname: Matsuura
authors.forename: Keita
authors.initials: K
authors.lastname: Kanki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kurimasa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
authors.forename: Goshi
authors.initials: G
authors.lastname: Shiota
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1 / Q000032:analysis; D033722:Equilibrative-Nucleoside Transporter 2 / Q000032:analysis*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; C438649:SLC29A1 protein, human; C438654:SLC29A2 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine