title: Functional analysis of [methyl-(3)H]choline uptake in glioblastoma cells: Influence of anti-cancer and central nervous system drugs.
abstract: Positron emission tomography (PET) and PET/computed tomography (PET-CT) studies with (11)C- or (18)F-labeled choline derivatives are used for PET imaging in glioblastoma patients. However, the nature of the choline transport system in glioblastoma is poorly understood. In this study, we performed a functional characterization of [methyl-(3)H]choline uptake and sought to identify the transporters that mediate choline uptake in the human glioblastoma cell lines A-172 and U-251MG. In addition, we examined the influence of anti-cancer drugs and central nervous system drugs on the transport of [methyl-(3)H]choline. High- and low-affinity choline transport systems were present in A-172 cells, U-251MG cells and astrocytes, and these were Na(+)-independent and pH-dependent. Cell viability in A-172 cells was not affected by choline deficiency. However, cell viability in U-251MG cells was significantly inhibited by choline deficiency. Both A-172 and U-251MG cells have two different choline transporters, choline transporter-like protein 1 (CTL1) and CTL2. In A-172 cells, CTL1 is predominantly expressed, whereas in U-251MG cells, CTL2 is predominantly expressed. Treatment with anti-cancer drugs such as cisplatin, etoposide and vincristine influenced [methyl-(3)H]choline uptake in U-251MG cells, but not A-172 cells. Central nervous system drugs such as imipramine, fluvoxamine, paroxetine, reboxetine, citalopram and donepezil did not affect cell viability or [methyl-(3)H]choline uptake. The data presented here suggest that CTL1 and CTL2 are functionally expressed in A-172 and U-251MG cells and are responsible for [methyl-(3)H]choline uptake that relies on a directed H(+) gradient as a driving force. Furthermore, while anti-cancer drugs altered [methyl-(3)H]choline uptake, central nervous system drugs did not affect [methyl-(3)H]choline uptake.
authors: Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjyuku, Shinjyuku-ku, Tokyo 160-0023, Japan.
authors: Chiaki
authors: C
authors: Taguchi
authors: Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjyuku, Shinjyuku-ku, Tokyo 160-8402, Japan; Department of Molecular Preventive Medicine, Tokyo Medical University, 6-1-1 Shinjyuku, Shinjyuku-ku, Tokyo 160-8402, Japan. Electronic address: inazu@tokyo-med.ac.jp.
authors: Masato
authors: M
authors: Inazu
authors: Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjyuku, Shinjyuku-ku, Tokyo 160-0023, Japan.
authors: Iwao
authors: I
authors: Saiki
authors: Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjyuku, Shinjyuku-ku, Tokyo 160-0023, Japan.
authors: Miki
authors: M
authors: Yara
authors: Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjyuku, Shinjyuku-ku, Tokyo 160-0023, Japan.
authors: Naomi
authors: N
authors: Hara
authors: Department of Molecular Preventive Medicine, Tokyo Medical University, 6-1-1 Shinjyuku, Shinjyuku-ku, Tokyo 160-8402, Japan.
authors: Tsuyoshi
authors: T
authors: Yamanaka
authors: Department of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjyuku, Shinjyuku-ku, Tokyo 160-0023, Japan.
authors: Hiroyuki
authors: H
authors: Uchino
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002794:Choline / Q000378:metabolism*; D005110:Extracellular Space / Q000737:chemistry; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014316:Tritium
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D002491:Central Nervous System Agents; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; C510732:SLC44A1 protein, human; C484524:SLC44A2 protein, human; C510731:SLC5A7 protein, human; D027981:Symporters; D014316:Tritium; D002794:Choline
keywords: Choline; Choline PET; Glioblastoma cells; Transporter