Choline transporter-like proteins CTLs/SLC44 family as a novel molecular target for cancer therapy

• Published in: Biopharmaceutics & drug disposition 2014-11, Vol.35 (8), p.431-449
• Main Author: Inazu, Masato
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; apoptosis; Apoptosis - drug effects; Biological Transport - drug effects; cancer; choline; Choline - metabolism; choline kinase; choline transporter-like protein; Humans; Membrane Transport Modulators - pharmacology; Membrane Transport Modulators - therapeutic use; Models, Biological; Molecular Targeted Therapy; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Organic Cation Transport Proteins - antagonists & inhibitors; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; transporter
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.1892

ABSTRACT Choline is essential for the synthesis of the major membrane phospholipid phosphatidylcholine (PC), the methyl donor betaine and the neurotransmitter acetylcholine (ACh). Elevated levels of choline and up‐regulated choline kinase activity have been detected in various cancers. Thus, the intracellular accumulation of choline through choline transporters is the rate‐limiting step in phospholipid metabolism and a prerequisite for cancer cell proliferation. Previous studies have demonstrated abnormalities in choline uptake and choline phospholipid metabolism in cancer cells using the imaging of cancer with positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). The aberrant choline metabolism in cancer cells is strongly correlated with their malignant progression. Using quantitative real‐time PCR, the mRNA expression of choline transporters was measured, and it was found that choline transporter‐like proteins CTLs/SLC44 family are highly expressed in various cancer cell lines. Choline uptake through CTLs is associated with cell viability, and the functional inhibition of CTLs could promote apoptotic cell death. Furthermore, non‐neuronal cholinergic systems that include CTLs‐mediated choline transport are associated with cell proliferation and their inhibition promotes apoptotic cell death in colon cancer, small cell lung cancer and human leukemic T‐cells. The identification of this new CTLs‐mediated choline transport system provides a potential new target for cancer therapy. Copyright © 2014 John Wiley & Sons, Ltd.