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: Chiaki Taguchi, Masato Inazu, Iwao Saiki, Miki Yara, Naomi Hara, Tsuyoshi Yamanaka, Hiroyuki Uchino
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 88 Issue 3 Pg. 303-12 (Apr 01 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 24530235 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD
• Antineoplastic Agents
• Central Nervous System Agents
• Membrane Glycoproteins
• Membrane Transport Proteins
• Organic Cation Transport Proteins
• RNA, Messenger
• Radiopharmaceuticals
• SLC44A1 protein, human
• SLC44A2 protein, human
• SLC5A7 protein, human
• Symporters
• Tritium
• Choline

Topics

• Antigens, CD (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Astrocytes (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Central Nervous System Agents (pharmacology)
• Choline (metabolism)
• Extracellular Space (chemistry)
• Glioblastoma (metabolism)
• Humans
• Hydrogen-Ion Concentration
• Membrane Glycoproteins (genetics, metabolism)
• Membrane Transport Proteins (genetics, metabolism)
• Organic Cation Transport Proteins (genetics, metabolism)
• RNA, Messenger (metabolism)
• Radiopharmaceuticals (metabolism)
• Symporters (genetics, metabolism)
• Tritium