title: Tocopherol transfer protein sensitizes prostate cancer cells to vitamin E.
abstract: Prostate cancer is a major cause of mortality in men in developed countries. It has been reported that the naturally occurring antioxidant α-tocopherol (vitamin E) attenuates prostate cancer cell proliferation in cultured cells and mouse models. We hypothesized that overexpression of the tocopherol transfer protein (TTP), a vitamin E-binding protein that regulates tocopherol status, will sensitize prostate cancer cells to the anti-proliferative actions of the vitamin. To test this notion, we manipulated the expression levels of TTP in cultured prostate cells (LNCaP, PC3, DU145, and RWPE-1) using overexpression and knockdown approaches. Treatment of cells with tocopherol caused a time- and dose-dependent inhibition of cell proliferation. Overexpression of TTP dramatically sensitized the cells to the apoptotic effects of α-tocopherol, whereas reduction ("knockdown") of TTP expression resulted in resistance to the vitamin. TTP levels also augmented the inhibitory effects of vitamin E on proliferation in semi-solid medium. The sensitizing effects of TTP were paralleled by changes in the intracellular accumulation of a fluorescent analog of vitamin E and by a reduction in intracellular levels of reactive oxygen species and were not observed when a naturally occurring, ligand binding-defective mutant of TTP was used. We conclude that TTP sensitizes prostate cancer cells to the anti-proliferative effects of vitamin E and that this activity stems from the ability of protein to increase the intracellular accumulation of the antioxidant. These observations support the notion that individual changes in the expression level or activity of TTP may determine the responsiveness of prostate cancer patients to intervention strategies that utilize vitamin E.
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Morley
authors.forename: Varsha
authors.initials: V
authors.lastname: Thakur
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
authors.forename: Robert
authors.initials: R
authors.lastname: Parker
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Atkinson
authors.forename: Jill
authors.initials: J
authors.lastname: Barnholtz-Sloan
authors.forename: Eric
authors.initials: E
authors.lastname: Klein
authors.forename: Danny
authors.initials: D
authors.lastname: Manor
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014810:Vitamin E / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D017382:Reactive Oxygen Species; D014815:Vitamins; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D011065:Poly(ADP-ribose) Polymerases; D024502:alpha-Tocopherol
references.citation: N Engl J Med. 2005 Jun 9;352(23):2379-88
references.pmid: 15829527
references.citation: Antioxid Redox Signal. 1999 Spring;1(1):71-81
references.pmid: 11225734
references.citation: Science. 1997 Mar 14;275(5306):1649-52
references.pmid: 9054359
references.citation: Br J Pharmacol. 2004 May;142(2):231-55
references.pmid: 15155533
references.citation: Biochemistry. 2006 Jul 11;45(27):8236-42
references.pmid: 16819822
references.citation: Int J Cancer. 1978 Mar 15;21(3):274-81
references.pmid: 631930
references.citation: FASEB J. 2004 Jun;18(9):1019-21
references.pmid: 15084515
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15185-90
references.pmid: 11752462
references.citation: Annu Rev Nutr. 1999;19:343-55
references.pmid: 10448528
references.citation: Biochemistry. 2004 Apr 13;43(14):4143-9
references.pmid: 15065857
references.citation: Nutr Cancer. 1997;28(1):30-5
references.pmid: 9200147
references.citation: Genes Cells. 2003 Oct;8(10):789-800
references.pmid: 14531858
references.citation: Cancer Res. 2004 Aug 15;64(16):5891-6
references.pmid: 15313934
references.citation: Arterioscler Thromb Vasc Biol. 1995 Mar;15(3):325-33
references.pmid: 7749842
references.citation: Biochem J. 1996 Sep 1;318 ( Pt 2):379-82
references.pmid: 8809022
references.citation: Neoplasia. 2007 Jan;9(1):68-80
references.pmid: 17325745
references.citation: Vitam Horm. 2007;76:45-65
references.pmid: 17628171
references.citation: Cancer Res. 2006 Oct 1;66(19):9519-26
references.pmid: 17018608
references.citation: Biochemistry. 2006 Jan 31;45(4):1075-81
references.pmid: 16430203
references.citation: Prostate. 2000 Sep 1;44(4):287-95
references.pmid: 10951493
references.citation: Cancer. 2000 Jul 1;89(1):123-34
references.pmid: 10897009
references.citation: Nutrition. 2001 Oct;17(10):799-805
references.pmid: 11684383
references.citation: Prostate. 2004 May 15;59(3):319-27
references.pmid: 15042608
references.citation: Curr Biol. 1997 Oct 1;7(10):794-7
references.pmid: 9368762
references.citation: Ital J Biochem. 1980 May-Jun;29(3):176-84
references.pmid: 6161107
references.citation: Cancer Res. 1983 Apr;43(4):1809-18
references.pmid: 6831420
references.citation: Ann Neurol. 1996 Feb;39(2):147-57
references.pmid: 8967745
references.citation: Clin Cancer Res. 2009 Mar 1;15(5):1593-600
references.pmid: 19223492
references.citation: Mol Cancer Ther. 2003 Aug;2(8):797-803
references.pmid: 12939470
references.citation: Proc Natl Acad Sci U S A. 2009 May 26;106(21):8683-8
references.pmid: 19429708
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2196-201
references.pmid: 10681450
references.citation: Am J Clin Nutr. 2002 Mar;75(3):555-60
references.pmid: 11864863
references.citation: Eur J Neurol. 2001 Sep;8(5):477-81
references.pmid: 11554913
references.citation: Arch Neurol. 1997 Jun;54(6):762-5
references.pmid: 9193212
references.citation: Invest Urol. 1979 Jul;17(1):16-23
references.pmid: 447482
references.citation: Prostate. 2007 Apr 1;67(5):463-71
references.pmid: 17252538
references.citation: J Biol Chem. 1999 Aug 13;274(33):23633-41
references.pmid: 10438546
references.citation: J Biol Chem. 2001 Jan 19;276(3):1669-72
references.pmid: 11076932
references.citation: J Natl Cancer Inst. 1997 Jan 1;89(1):40-8
references.pmid: 8978405
references.citation: J Natl Cancer Inst. 2005 Mar 2;97(5):396-9
references.pmid: 15741576
references.citation: Ann N Y Acad Sci. 2004 Dec;1031:22-39
references.pmid: 15753131
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13830-4
references.pmid: 11095717
references.citation: JAMA. 2009 Jan 7;301(1):39-51
references.pmid: 19066370
references.citation: Ann Neurol. 1998 Feb;43(2):273
references.pmid: 9485073
references.citation: Alzheimer Dis Assoc Disord. 1996 Fall;10(3):132-40
references.pmid: 8876776
references.citation: Biochemistry. 2008 Jan 15;47(2):744-52
references.pmid: 18095660
references.citation: Cell. 1974 Dec;3(4):355-9
references.pmid: 4442124
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12437-41
references.pmid: 9356467
references.citation: J Natl Cancer Inst. 1999 Jul 21;91(14):1227-32
references.pmid: 10413424
references.citation: J Biol Chem. 1998 Dec 11;273(50):33533-9
references.pmid: 9837934
references.citation: Eur J Biochem. 2000 Sep;267(17):5421-6
references.pmid: 10951200
references.citation: Eur J Cancer. 2005 Jan;41(1):61-70
references.pmid: 15617991
references.citation: Cancer Res. 1997 Jun 15;57(12):2410-4
references.pmid: 9192818
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 Jun;12(6):518-26
references.pmid: 12814997
references.citation: Carcinogenesis. 1997 Jun;18(6):1215-23
references.pmid: 9214605
references.citation: Nat Genet. 1995 Feb;9(2):141-5
references.pmid: 7719340
references.citation: Cancer Res. 2009 Feb 15;69(4):1429-38
references.pmid: 19190344
references.citation: Biochemistry. 2003 Jun 3;42(21):6467-74
references.pmid: 12767229
references.citation: Cancer Res. 2008 Mar 15;68(6):1777-85
references.pmid: 18339858
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1420-4
references.pmid: 18230739
references.citation: J Biol Chem. 2008 Jun 27;283(26):17797-804
references.pmid: 18458085
references.citation: Cancer Lett. 2009 Sep 18;282(2):125-36
references.pmid: 19185987
references.citation: Mitochondrion. 2003 Aug;3(1):29-38
references.pmid: 16120342
references.citation: Bioorg Med Chem. 2006 Jun 1;14(11):3721-36
references.pmid: 16481173
references.citation: Am Biotechnol Lab. 1993 Mar;11(4):48-50
references.pmid: 7763491
references.citation: Biochem Cell Biol. 1992 Jun;70(6):486-8
references.pmid: 1449715
references.citation: Am J Hum Genet. 1998 Feb;62(2):301-10
references.pmid: 9463307
references.citation: Cancer Res. 2001 Aug 15;61(16):6025-8
references.pmid: 11507046
references.citation: J Lipid Res. 2005 Oct;46(10):2072-82
references.pmid: 16024914