Tocopherol transfer protein sensitizes prostate cancer cells to vitamin E.
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.
Morley
Samantha
S
Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Thakur
Varsha
V
Danielpour
David
D
Parker
Robert
R
Arai
Hiroyuki
H
Atkinson
Jeffrey
J
Barnholtz-Sloan
Jill
J
Klein
Eric
E
Manor
Danny
D
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
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
N Engl J Med. 2005 Jun 9;352(23):2379-88
15829527
Antioxid Redox Signal. 1999 Spring;1(1):71-81
11225734
Science. 1997 Mar 14;275(5306):1649-52
9054359
Br J Pharmacol. 2004 May;142(2):231-55
15155533
Biochemistry. 2006 Jul 11;45(27):8236-42
16819822
Int J Cancer. 1978 Mar 15;21(3):274-81
631930
FASEB J. 2004 Jun;18(9):1019-21
15084515
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15185-90
11752462
Annu Rev Nutr. 1999;19:343-55
10448528
Biochemistry. 2004 Apr 13;43(14):4143-9
15065857
Nutr Cancer. 1997;28(1):30-5
9200147
Genes Cells. 2003 Oct;8(10):789-800
14531858
Cancer Res. 2004 Aug 15;64(16):5891-6
15313934
Arterioscler Thromb Vasc Biol. 1995 Mar;15(3):325-33
7749842
Biochem J. 1996 Sep 1;318 ( Pt 2):379-82
8809022
Neoplasia. 2007 Jan;9(1):68-80
17325745
Vitam Horm. 2007;76:45-65
17628171
Cancer Res. 2006 Oct 1;66(19):9519-26
17018608
Biochemistry. 2006 Jan 31;45(4):1075-81
16430203
Prostate. 2000 Sep 1;44(4):287-95
10951493
Cancer. 2000 Jul 1;89(1):123-34
10897009
Nutrition. 2001 Oct;17(10):799-805
11684383
Prostate. 2004 May 15;59(3):319-27
15042608
Curr Biol. 1997 Oct 1;7(10):794-7
9368762
Ital J Biochem. 1980 May-Jun;29(3):176-84
6161107
Cancer Res. 1983 Apr;43(4):1809-18
6831420
Ann Neurol. 1996 Feb;39(2):147-57
8967745
Clin Cancer Res. 2009 Mar 1;15(5):1593-600
19223492
Mol Cancer Ther. 2003 Aug;2(8):797-803
12939470
Proc Natl Acad Sci U S A. 2009 May 26;106(21):8683-8
19429708
Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2196-201
10681450
Am J Clin Nutr. 2002 Mar;75(3):555-60
11864863
Eur J Neurol. 2001 Sep;8(5):477-81
11554913
Arch Neurol. 1997 Jun;54(6):762-5
9193212
Invest Urol. 1979 Jul;17(1):16-23
447482
Prostate. 2007 Apr 1;67(5):463-71
17252538
J Biol Chem. 1999 Aug 13;274(33):23633-41
10438546
J Biol Chem. 2001 Jan 19;276(3):1669-72
11076932
J Natl Cancer Inst. 1997 Jan 1;89(1):40-8
8978405
J Natl Cancer Inst. 2005 Mar 2;97(5):396-9
15741576
Ann N Y Acad Sci. 2004 Dec;1031:22-39
15753131
Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13830-4
11095717
JAMA. 2009 Jan 7;301(1):39-51
19066370
Ann Neurol. 1998 Feb;43(2):273
9485073
Alzheimer Dis Assoc Disord. 1996 Fall;10(3):132-40
8876776
Biochemistry. 2008 Jan 15;47(2):744-52
18095660
Cell. 1974 Dec;3(4):355-9
4442124
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12437-41
9356467
J Natl Cancer Inst. 1999 Jul 21;91(14):1227-32
10413424
J Biol Chem. 1998 Dec 11;273(50):33533-9
9837934
Eur J Biochem. 2000 Sep;267(17):5421-6
10951200
Eur J Cancer. 2005 Jan;41(1):61-70
15617991
Cancer Res. 1997 Jun 15;57(12):2410-4
9192818
Cancer Epidemiol Biomarkers Prev. 2003 Jun;12(6):518-26
12814997
Carcinogenesis. 1997 Jun;18(6):1215-23
9214605
Nat Genet. 1995 Feb;9(2):141-5
7719340
Cancer Res. 2009 Feb 15;69(4):1429-38
19190344
Biochemistry. 2003 Jun 3;42(21):6467-74
12767229
Cancer Res. 2008 Mar 15;68(6):1777-85
18339858
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1420-4
18230739
J Biol Chem. 2008 Jun 27;283(26):17797-804
18458085
Cancer Lett. 2009 Sep 18;282(2):125-36
19185987
Mitochondrion. 2003 Aug;3(1):29-38
16120342
Bioorg Med Chem. 2006 Jun 1;14(11):3721-36
16481173
Am Biotechnol Lab. 1993 Mar;11(4):48-50
7763491
Biochem Cell Biol. 1992 Jun;70(6):486-8
1449715
Am J Hum Genet. 1998 Feb;62(2):301-10
9463307
Cancer Res. 2001 Aug 15;61(16):6025-8
11507046
J Lipid Res. 2005 Oct;46(10):2072-82
16024914