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

Biopharmaceutics and Drug Disposition

Volumn 35, Issue 8, 2014, Pages 431-449

  Inazu, Masato ^a  

^a TOKYO MEDICAL UNIVERSITY   (Japan)

Author keywords

Apoptosis; Cancer; Choline; Choline Kinase; Choline Transporter Like Protein; Transporter

Indexed keywords

ACETYLCHOLINE; ANTINEOPLASTIC AGENT; CARRIER PROTEINS AND BINDING PROTEINS; CASPASE 3; CHOLINE; CHOLINE KINASE; CHOLINE TRANSPORTER LIKE PROTEIN; CHOLINE TRANSPORTER LIKE PROTEIN 1; CHOLINE UPTAKE INHIBITOR; UNCLASSIFIED DRUG; AGENTS AFFECTING WATER, MOLECULE OR ION TRANSPORT; ISOPROTEIN; LEUKOCYTE ANTIGEN; ORGANIC CATION TRANSPORTER; SLC44A1 PROTEIN, HUMAN; TUMOR PROTEIN;

ACTIVE TRANSPORT; APOPTOSIS; BREAST CANCER; CANCER CELL; CELL PROLIFERATION; CELL VIABILITY; CHOLINE UPTAKE; CHOLINERGIC NERVE CELL; CHOLINERGIC SYSTEM; COLON CANCER; COMPUTER ASSISTED EMISSION TOMOGRAPHY; DNA METHYLATION; DNA REPAIR; HUMAN; LEUKEMIA; MOLECULARLY TARGETED THERAPY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PHOSPHOLIPID METABOLISM; POSITRON EMISSION TOMOGRAPHY; PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; REAL TIME POLYMERASE CHAIN REACTION; REVIEW; SMALL CELL LUNG CANCER; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOLOGICAL MODEL; DRUG EFFECTS; GENETICS; METABOLISM; NEOPLASMS; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; ANTIGENS, CD; ANTINEOPLASTIC AGENTS; APOPTOSIS; BIOLOGICAL TRANSPORT; CHOLINE; HUMANS; MEMBRANE TRANSPORT MODULATORS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; NEOPLASMS; ORGANIC CATION TRANSPORT PROTEINS; PROTEIN ISOFORMS;

EID: 84915812910     PISSN: 01422782     EISSN: 1099081X     Source Type: Journal    
DOI: 10.1002/bdd.1892     Document Type: Review

References (123)

1. Michel V, Yuan Z, Ramsubir S, Bakovic M. Choline transport for phospholipid synthesis. Exp Biol Med 2006; 231: 490-504
2. Apparsundaram S, Ferguson SM, George AL Jr, Blakely RD. Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem Biophys Res Commun 2000; 276: 862-867
3. Okuda T, Haga T, Kanai Y, Endou H, Ishihara T, Katsura I. Identification and characterization of the high-affinity choline transporter. Nature Neurosci 2000; 3: 120-125
4. Burckhardt G, Wolff NA. Structure of renal organic anion and cation transporters. Am J Physiol Renal Physiol 2000; 278: F853-F866
5. Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 2007; 24: 1227-1251
6. Gorboulev V, Ulzheimer JC, Akhoundova A, et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 1997; 16: 871-881
7. Gründemann D, Schechinger B, Rappold GA, Schömig E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci 1998; 1: 349-351
8. Gründemann D, Liebich G, Kiefer N, Köster S, Schömig E. Selective substrates for non-neuronal monoamine transporters. Mol Pharmacol 1999; 56: 1-10
9. Kekuda R, Prasad PD, Wu X, et al. Cloning and functional characterization of a potentialsensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 1998; 273: 15971-15979
10. Wu X, Kekuda R, Huang W, et al. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 1998; 273: 32776-32786
11. O'Regan S, Traiffort E, Ruat M, Cha N, Compaore D, Meunier FM. An electric lobe suppressor for a yeast choline transport mutation belongs to a new family of transporter-like proteins. Proc Natl Acad Sci USA 2000; 97: 1835-1840
12. O'Regan S, Meunier FM. Selection and characterization of the choline transport mutation suppressor from Torpedo electric lobe, CTL1. Neurochem Res 2003; 28: 551-555
13. Inazu M, Takeda H, Matsumiya T. Molecular and functional characterization of a Na+-independent choline transporter in rat astrocytes. J Neurochem 2005; 94: 1427-1437
14. Uchida Y, InazuM, TakedaH, Yamada T, TajimaH, Matsumiya T. Expression and functional characterization of choline transporter in human keratinocytes. J Pharm Sci 2009; 109: 102-109
15. Kouji H, Inazu M, Yamada T, Tajima H, Aoki T, Matsumiya T. Molecular and functional characterization of choline transporter in human colon carcinoma HT-29 cells. Arch Biochem Biophys 2009; 483: 90-98
16. Nair TS, Kozma KE, Hoefling NL, et al. Identification and characterization of choline transporterlike protein 2, an inner ear glycoprotein of 68 and 72 kDa that is the target of antibody-induced hearing loss. J Neurosci 2004; 24: 1772-1779
17. Yabuki M, Inazu M, Yamada T, Tajima H, Matsumiya T. Molecular and functional characterization of choline transporter in rat renal tubule epithelial NRK-52E cells. Arch Biochem Biophys 2009; 485: 88-96
18. Nakamura T, Fujiwara R, Ishiguro N, et al. Involvement of choline transporter-like proteins, CTL1 and CTL2, in glucocorticoid-induced acceleration of phosphatidylcholine synthesis via increased choline uptake. Biol Pharm Bull 2010; 33: 691-696
19. Kommareddi PK, Nair TS, Thang LV, et al. Isoforms, expression, glycosylation, and tissue distribution of CTL2/SLC44A2. Protein J 2010; 29: 417-426
20. Katz-Brull R, Degani H. Kinetics of choline transport and phosphorylation in human breast cancer cells; NMR application of the zero trans method. Anticancer Res 1996; 16: 1375-1380
21. Glunde K, Serkova NJ. Therapeutic targets and biomarkers identified in cancer choline phospholipid metabolism. Pharmacogenomics 2006; 7: 1109-1123
22. Cai H, Erhardt P, Troppmair J, et al. Hydrolysis of phosphatidylcholine couples Ras to activation of Raf protein kinase during mitogenic signal transduction. Mol Cell Biol 1993; 13: 7645-7651
23. Kwee SA, Wei H, Sesterhenn I, Yun D, Coel MN. Localization of primary prostate cancer with dual-phase 18F-fluorocholine PET. J Nucl Med 2006; 47: 262-269
24. Hara T, Kondo T, Hara T, Kosaka N. Use of 18Fcholine and 11C-choline as contrast agents in positron emission tomography imaging-guided stereotactic biopsy sampling of gliomas. J Neurosurg 2003; 99: 474-479
25. Möller-Hartmann W, Herminghaus S, Krings T, et al. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 2002; 44: 371-381
26. Gillies RJ, Morse DL. In vivo magnetic resonance spectroscopy in cancer. Annu Rev Biomed Eng 2005; 7: 287-326
27. Glunde K, Jiang L, Moestue SA, Gribbestad IS. Magnetic resonance spectroscopy and imaging guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer. NMR Biomed 2011; 24: 673-690
28. Glunde K, Jie C, Bhujwalla ZM. Molecular causes of the aberrant choline phospholipid metabolism in breast cancer. Cancer Res 2004; 64: 4270-4276
29. Glunde K, Jacobs MA, Bhujwalla ZM. Choline metabolism in cancer: implications for diagnosis and therapy. Expert Rev Mol Diagn 2006; 6: 821-829
30. Eliyahu G, Kreizman T, Degani H. Phosphocholine as a biomarker of breast cancer: molecular and biochemical studies. Int J Cancer 2007; 120: 1721-1730
31. Hara T, Kosaka N, Shinoura N, Kondo T. PET imaging of brain tumor with [methyl-11C]choline. J Nucl Med 1997; 38: 842-847
32. Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11-choline. J Nucl Med 1998; 39: 990-995
33. Hara T, Inagaki K, Kosaka N, Morita T. Sensitive detection of mediastinal lymph node metastasis of lung cancer with 11C-choline PET. J Nucl Med 2000; 41: 1507-1513
34. Kobori O, Kirihara Y, Kosaka N, Hara T. Positron emission tomography of esophageal carcinoma using 11C-choline and 18F-fluorodeoxyglucose: a novel method of preoperative lymph node staging. Cancer 1999; 86: 1638-1648
35. Sweet DH, Miller DS, Pritchard JB. Ventricular choline transport a role for organic cation transporter 2 expressed in choroid plexus. J Biol Chem 2001; 276: 41611-416119
36. Zeisel SH, da Costa KA, Franklin PD, et al. Choline: an essential nutrient for humans. FASEB J 1991; 5: 2093-2098
37. Zeisel SH. Choline: essential for brain development and function. Adv Pediatr 1997; 44: 263-295
38. Kent C. Regulatory enzymes of phosphatidylcholine biosynthesis: a personal perspective. Biochim Biophys Acta 2005; 1733: 53-66
39. Aoyama C, Liao H, Ishidate K. Structure and function of choline kinase isoforms in mammalian cells. Prog Lipid Res 2004; 43: 266-281
40. McMaster CR, Bell RM. CDP-choline:1,2-diacylglycerolcholinephospho-transferase. Biochim Biophys Acta 1997; 1348: 100-110
41. Vance JE, Vance DE. Metabolic insights into phospholipids function using gene-targeted mice. J Biol Chem 2005; 280: 10877-10880
42. Jackowski S, Fagone P. CTP:phosphocholine cytidylyltransferase: paving the way from gene to membrane. J Biol Chem 2005; 280: 853-856
43. Zeisel SH, Blusztajn JK. Choline and human nutrition. Annu Rev Nutr 1994; 14: 269-296
44. Fisher MC, Zeisel SH, Mar MH, Sadler TW. Inhibitors of choline uptake and metabolism cause developmental abnormalities in neurulating mouse embryos. Teratology 2001; 64: 114-122
45. Balassiano K, Lima S, JenabM, et al. Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Cancer Lett 2011; 311: 85-95
46. Wessler I, Kirkpatrick CJ. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 2008; 154: 1558-1571
47. Kawashima K, Fujii T. Extraneuronal cholinergic system in lymphocytes. Pharmacol Ther 2000; 86: 29-48
48. Takalkar AM, El-Haddad G, Lilien DL. FDG-PET and PET/CT-Part II. Indian J Radiol Imaging 2008; 18: 17-36
49. Ramirez de Molina A, Gutierrez R, Ramos MA, et al. Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy. Oncogene 2002; 21: 4317-4322
50. Glunde K, Bhujwalla ZM, Ronen SM. Choline metabolism in malignant transformation. Nat Rev Cancer 2011; 11: 835-848
51. Wu G, Vance DE. Choline kinase and its function. Biochem Cell Biol 2010; 88: 559-564
52. Treglia G, Giovannini E, Di Franco D, et al. The role of positron emission tomography using carbon-11 and fluorine-18 choline in tumors other than prostate cancer: a systematic review. Ann Nucl Med 2012; 26: 451-461
53. Fuccio C, Rubello D, Castellucci P, Marzola MC, Fanti S. Choline PET/CT for prostate cancer: main clinical applications. Eur J Radiol 2011; 80: e50-e56
54. Kwee SA, DeGrado TR, Talbot JN, Gutman F, Coel MN. Cancer imaging with fluorine-18-labeled choline derivatives. Semin Nucl Med 2007; 37: 420-428
55. Mertens K, Slaets D, Lambert B, Acou M, De Vos F, Goethals I. PET with 18F-labelled choline-based tracers for tumour imaging: a review of the literature. Eur J Nucl MedMol Imaging 2010; 37: 2188-2193
56. Ross B, Michaelis T. Clinical applications of magnetic resonance spectroscopy. Magn Reson Q 1994; 10: 191-247
57. Nelson SJ. Analysis of volume MRI and MR spectroscopic imaging data for the evaluation of patients with brain tumors. Magn Reson Med 2001; 46: 228-239
58. Meisamy S, Bolan PJ, Baker EH, et al. Adding in vivo quantitative 1H MR spectroscopy to improve diagnostic accuracy of breast MR imaging: preliminary results of observer performance study at 4.0 T. Radiology 2005; 236: 465-475
59. Stanwell P, Gluch L, Clark D, et al. Specificity of choline metabolites for in vivo diagnosis of breast cancer using 1H MRS at 1.5 T. Eur Radiol 2005; 15: 1037-1043
60. Ramirez de Molina A, Gutierrez R, Ramos MA, et al. Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy. Oncogene 2002; 21: 4317-4322
61. Rodriguez-Gonzalez A, Ramirez de Molina A, Fernandez F, Lacal JC. Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action. Oncogene 2004; 23: 8247-8259
62. Baek HM, Chen JH, Nie K, et al. Predicting pathologic response to neoadjuvant chemotherapy in breast cancer by using MR imaging and quantitative 1HMR spectroscopy. Radiology 2009; 251: 653-662
63. Glunde K, Jie C, Bhujwalla ZM. Molecular causes of the aberrant choline phospholipid metabolism in breast cancer. Cancer Res 2004; 64: 4270-4276
64. Katz-Brull R, Lavin PT, Lenkinski RE. Clinical utility of proton magnetic resonance spectroscopy in characterizing breast lesions. J Natl Cancer Inst 2002; 94: 1197-1203
65. NegendankW. Studies of human tumors by MRS: a review. NMR Biomed 1992; 5: 303-324
66. Kurhanewicz J, Vigneron DB, Hricak H, et al. Prostate cancer: metabolic response to cryosurgery as detected with 3D H-1 MR spectroscopic imaging. Radiology 1996; 200: 489-496
67. Bezabeh T, Smith IC, Krupnik E, et al. Diagnostic potential for cancer via 1H magnetic resonance spectroscopy of colon tissue. Anticancer Res 1996; 16: 1553-1558
68. Nelson SJ. Analysis of volume MRI and MR spectroscopic imaging data for the evaluation of patients with brain tumors. Magn Reson Med 2001; 46: 228-239
69. Ruiz-Cabello J, Cohen JS. Phospholipid metabolites as indicators of cancer cell function. NMR Biomed 1992; 5: 226-233
70. Ting YL, Sherr D, Degani H. Variations in energy and phospholipid metabolism in normal and cancer human mammary epithelial cells. Anticancer Res 1996; 16: 1381-1388
71. Bolan PJ, DelaBarre L, Baker EH, et al. Eliminating spurious lipid sidebands in 1H MRS of breast lesions. Magn Reson Med 2002; 48: 215-222
72. Aboagye EO, Bhujwalla ZM. Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Res 1999; 59: 80-84
73. Jagannathan NR, Kumar M, Seenu V, et al. Evaluation of total choline from in vivo volume localized proton MR spectroscopy and its response to neoadjuvant chemotherapy in locally advanced breast cancer. Br J Cancer 2001; 84: 1016-1022
74. Ferguson SM, Bazalakova M, Savchenko V, Tapia JC, Wright J, Blakely RD. Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice. Proc Natl Acad Sci USA 2004; 101: 8762-8767
75. Haberberger RV, Pfeil U, Lips KS, KummerW. Expression of the high-affinity choline transporter, CHT1, in the neuronal and non-neuronal cholinergic system of human and rat skin. J Invest Dermatol 2002; 119: 943-948
76. Pfeil U, Lips KS, Eberling L, Grau V, Haberberger RV, Kummer W. Expression of the high-affinity choline transporter, CHT1, in the rat trachea. Am J Respir Cell Mol Biol 2003; 28: 473-477
77. Okuda M, Saito H, Urakami Y, Takano M, Inui K. cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem Biophys Res Commun 1996; 224: 500-507
78. Traiffort E, Ruat M, O'Regan S, Meunier FM. Molecular characterization of the family of choline transporter-like proteins and their splice variants. J Neurochem 2005; 92: 1116-1125
79. Machova E, O'Regan S, Newcombe J, et al. Detection of choline transporter-like 1 protein CTL1 in neuroblastoma glioma cells and in the CNS, and its role in choline uptake. J Neurochem 2009; 110: 1297-1309
80. Yuan Z, Wagner L, Poloumienko A, Bakovic M. Identification and expression of a mouse musclespecific CTL1 gene. Gene 2004; 341: 305-312
81. Yuan Z, Tie A, Tarnopolsky M, Bakovic M. Genomic organization, promoter activity, and expression of the human choline transporter-like protein 1. Physiol Genomics 2006; 26: 76-90
82. Beyer LA, Galano MM, Nair TS, et al. Age-related changes in expression of CTL2/SLC44A2 and its isoforms in the mouse inner ear. Hear Res 2011; 282: 63-68
83. Greinacher A, Wesche J, Hammer E, et al. Characterization of the human neutrophil alloantigen-3a. Nat Med 2010; 16: 45-48
84. Traiffort E, O'Regan S, Ruat M. The choline transporter-like family SLC44: properties and roles in human diseases. Mol Aspects Med 2013; 34: 646-654
85. Yamada T, Inazu M, Tajima H, Matsumiya T. Functional expression of choline transporter-like protein 1 (CTL1) in human neuroblastoma cells and its link to acetylcholine synthesis. Neurochem Int 2011; 58: 354-365
86. Inazu M, Yamada T, Kubota N, Yamanaka T. Functional expression of choline transporter-like protein 1 (CTL1) in small cell lung carcinoma cells: a target molecule for lung cancer therapy. Pharmacol Res 2013; 76: 119-131
87. Van Asten JJ, Cuijpers V, Hulsbergen-van de Kaa C, et al. High resolution magic angle spinning NMR spectroscopy for metabolic assessment of cancer presence and Gleason score in human prostate needle biopsies. MAGMA 2008; 21: 435-442
88. Keshari KR, Tsachres H, Iman R, et al. Correlation of phospholipid metabolites with prostate cancer pathologic grade, proliferative status and surgical stage-impact of tissue environment. NMR Biomed 2011; 24: 691-699
89. Rinnab L, Blumstein NM, Mottaghy FM, et al. 11Ccholine positron-emission tomography/computed tomography and transrectal ultrasonography for staging localized prostate cancer. BJU Int 2007; 99: 1421-1426
90. Reske SN, Blumstein NM, Neumaier B, et al. Imaging prostate cancer with 11C-choline PET/CT. J Nucl Med 2006; 47: 1249-1254
91. Müller SA, Holzapfel K, Seidl C, Treiber U, Krause BJ, Senekowitsch-Schmidtke R. Characterization of choline uptake in prostate cancer cells following bicalutamide and docetaxel treatment. Eur J Nucl Med Mol Imaging 2009; 36: 1434-1442
92. Inazu M, Ishikawa T, Takase A, et al. Functional characterization of choline transporter in human prostate cancer cells. J Pharmacol Sci 2010; 112: (Suppl.) 218P.
93. Ruiz-Cabello J, Cohen JS. Phospholipid metabolites as indicators of cancer cell function. NMR Biomed 1992; 5: 226-233
94. Ting YL, Sherr D, Degani H. Variations in energy and phospholipid metabolism in normal and cancer human mammary epithelial cells. Anticancer Res 1996; 16: 1381-1388
95. Aboagye EO, Bhujwalla ZM. Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Res 1999; 59: 80-84
96. Katz-Brull R, Seger D, Rivenson-Segal D, Rushkin E, Degani H. Metabolic markers of breast cancer: enhanced choline metabolism and reduced cholineether-phospholipid synthesis. Cancer Res 2002; 62: 1966-1970
97. Hara T, Bansal A, DeGrado TR. Choline transporter as a novel target for molecular imaging of cancer. Mol Imaging 2006; 5: 498-509
98. Ramirez deMolina A, Banez-Coronel M, Gutierrez R, et al. Choline kinase activation is a critical requirement for the proliferation of primary human mammary epithelial cells and breast tumor progression. Cancer Res 2004; 64: 6732-6739
99. Yoshimoto M, Waki A, Obata A, Furukawa T, Yonekura Y, Fujibayashi Y. Radiolabeled choline as a proliferation marker: comparison with radiolabeled acetate. Nucl Med Biol 2004; 31: 859-865
100. Liu D, Hutchinson OC, Osman S, Price P, Workman P, Aboagye EO. Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin. Br J Cancer 2002; 87: 783-789
101. Cheng K, Samimi R, Xie G, et al. Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation. Am J Physiol Gastrointest Liver Physiol 2008; 295: G591-G597
102. Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Fam Physician 2007; 75: 56-63
103. Wisnivesky JP, Halm EA, Bonomi M, Smith C, Mhango G, Bagiella E. Postoperative radiotherapy for elderly patients with stage III lung cancer. Cancer 2012; 118: 4478-4485
104. Russo P, Catassi A, Cesario A, Servent D. Development of novel therapeutic strategies for lung cancer: targeting the cholinergic system. Curr Med Chem 2006; 13: 3493-3512
105. Song P, Sekhon HS, Jia Y, et al. Acetylcholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma. Cancer Res 2003; 63: 214-221
106. Song P, Sekhon HS, Lu A, et al. M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen activated protein kinase phosphorylation induced by acetylcholine secretion. Cancer Res 2007; 67: 3936-3944
107. Zhang S, Togo S, Minakata K, et al. Distinct roles of cholinergic receptors in small cell lung cancer cells. Anticancer Res 2010; 30: 97-106
108. Wang T, Li J, Chen F, et al. Choline transporters in human lung adenocarcinoma: expression and functional implications. Acta Biochim Biophys Sin (Shanghai) 2007; 39: 668-674
109. Song P, Rekow SS, Singleton CA, et al. Choline transporter-like protein 4 (CTL4) links to nonneuronal acetylcholine synthesis. J Neurochem 2013; 126: 451-461
110. Kawashima K, Fujii T, Moriwaki Y, Misawa H, Horiguchi K. Reconciling neuronally and nonneuronally derived acetylcholine in the regulation of immune function. Ann N Y Acad Sci 2012; 1261: 7-17
111. Kawashima K, Fujii T. Basic and clinical aspects of non-neuronal acetylcholine: overview of nonneuronal cholinergic systems and their biological significance. J Pharmacol Sci 2008; 106: 167-173
112. Kawashima K, Fujii T. The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci 2003; 74: 675-696
113. Fujii T, Okuda T, Haga T, Kawashima K. Detection of the high-affinity choline transporter in the MOLT-3 human leukemic T-cell line. Life Sci 2003; 72(18-19): 2131-2134
114. Albright CD, Liu R, Bethea TC, Da Costa KA, Salganik RI, Zeisel SH. Choline deficiency induces apoptosis in SV40-immortalized CWSV-1 rat hepatocytes in culture. FASEB J 1996; 10: 510-516
115. Yen CL, Mar MH, Zeisel SH. Choline deficiencyinduced apoptosis in PC12 cells is associated with diminished membrane phosphatidylcholine and sphingomyelin, accumulation of ceramide and diacylglycerol, and activation of a caspase. FASEB J 1999; 13: 135-142
116. Yen CL, Mar MH, Meeker RB, Fernandes A, Zeisel SH. Choline deficiency induces apoptosis in primary cultures of fetal neurons. FASEB J 2001; 15: 1704-1710
117. Marchesini N, Hannun YA. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 2004; 82: 27-44
118. Ruvolo PP. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 2001; 15: 1153-1160
119. Vaux DL, Strasser A. The molecular biology of apoptosis. Proc Natl Acad Sci USA 1996; 93: 2239-2244
120. Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science 1996; 274: 1855-1859
121. Spiegel S, Foster D, Kolesnick R. Signal transduction through lipid second messengers. Curr Opin Cell Biol 1996; 8: 159-167
122. Nicholson DW, All A, Thornberry NA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995; 376: 37-43
123. Sanchez-Lopez E,Zimmerman T,GomezDel Pulgar T, Moyer MP, Lacal Sanjuan JC, Cebrian A. Choline kinase inhibition induces exacerbated endoplasmic reticulum stress and triggers apoptosis via CHOP in cancer cells. Cell Death Dis 2013; 4: e933