Overexpression of 12/15-lipoxygenase, an ortholog of human 15-lipoxygenase-1, in the prostate tumors of TRAMP mice.
Changes in the expression and activity of lipid-metabolizing enzymes, including the linoleic acid (LA)-metabolizing enzyme 15-lipoxygenase-1 (15-LO-1), may play a role in the development and progression of human prostate carcinoma (PCa). We reported that human 15-LO-1 (designated as leukocyte type 12-LO or 12/15-LO in mouse) is expressed in human prostate and increased in PCa, particularly high-grade PCa. Genetically engineered mouse (GEM) models of PCa could facilitate the study of this gene and its regulation and function in PCa progression. In this study, we examine the protein expression and enzyme activity levels of 12/15-LO associated with PCa progression in the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) model of PCa. This GEM model develops prostatic intraepithelial neoplasia (PIN), followed by invasive gland-forming PCa and invasive and metastatic less differentiated PCa, with neuroendocrine (NE) differentiation (NE Ca). In the wild-type and TRAMP prostates, the most prominent LA metabolite was 13-hydroxyoctadecadienoic acid (13-HODE). Lesser amounts of 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid (HETE) were made from arachidonic acid (AA). In TRAMP prostates, 12/15-LO activity was increased compared to wild type at 20, 29, 39, and 49 weeks, as assessed by LA conversion to 13-HODE, and by AA conversion to 12/15-HETE, respectively. Immunostaining demonstrated that the increased capacity to generate 13-HODE was paralleled by an increase in neoplastic epithelial expression of 12/15-LO in PIN and invasive carcinomas. In conclusion, although there is a basal 12/15-LO activity in the wild-type mouse prostate, there is a marked increase in the expression of 12/15-LO with TRAMP PCa progression, paralleling our previously reported increased expression of the ortholog 15-LO-1 in high-grade human PCa. Thus, 12/15-LO and LA metabolism in the TRAMP model shares similarities to human PCa, and may allow to confirm a role for LA metabolism and other biologic functions of 15-LO-1 in human PCa. In addition, the TRAMP model will serve as a tool for testing the suitability of 12/15-LO-and ultimately human 15-LO--as a therapeutic target during PCa progression.
Kelavkar
Uddhav P
UP
Department of Urology, University of Pittsburgh and Cancer Institute (UPCI), Pittsburgh, PA 15232, USA. kelavkarup@msx.upmc.edu
Glasgow
Wayne
W
Olson
Sandra J
SJ
Foster
Barbara A
BA
Shappell
Scott B
SB
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D019787:Linoleic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D015854:Up-Regulation
C475064:12-15-lipoxygenase; D016718:Arachidonic Acid; D019787:Linoleic Acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
Cancer Res. 1999 May 1;59(9):2203-9
10232609
Cancer Res. 2001 Jan 15;61(2):497-503
11212240
Neoplasia. 2004 Jan-Feb;6(1):41-52
15068670
Urology. 1995 Aug;46(2):227-37
7624992
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4378-83
10200270
Cancer Res. 1975 Nov;35(11 Pt. 2):3240-5
1192400
Carcinogenesis. 2000 Oct;21(10):1777-87
11023533
Lab Invest. 1998 Mar;78(3):319-33
9520945
Clin Exp Metastasis. 1993 May;11(3):243-50
7682484
Cancer Res. 2004 Mar 15;64(6):2270-305
15026373
Cancer Res. 2001 Sep 15;61(18):6777-82
11559550
J Urol. 2004 Jan;171(1):439-42
14665950
Am J Pathol. 1999 Jul;155(1):235-45
10393855
Biochem Biophys Res Commun. 1997 Feb 3;231(1):111-6
9070230
Hum Pathol. 2000 Sep;31(9):1146-54
11014584
Anticancer Res. 1998 May-Jun;18(3A):1429-34
9673351
J Biol Chem. 1997 Sep 26;272(39):24410-6
9305900
Cancer Res. 2003 May 1;63(9):2256-67
12727848
Prostaglandins Leukot Essent Fatty Acids. 1998 May;58(5):339-46
9690711
J Biol Chem. 2001 Sep 14;276(37):34545-52
11447213
Cancer Lett. 2003 Mar 10;191(2):125-35
12618325
J Biol Chem. 1998 Aug 21;273(34):21569-77
9705287
Biochem Biophys Res Commun. 1997 Oct 29;239(3):775-81
9367845
J Biol Chem. 1994 May 13;269(19):13979-87
8188678
J Urol. 2004 Feb;171(2 Pt 2):S19-24
14713748
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3439-43
7724580
Front Biosci. 1998 Jun 8;3:E81-8
9616130
Prostate Cancer Prostatic Dis. 1999 Mar;2(2):70-75
12496841
FEBS Lett. 1993 Sep 13;330(2):156-60
8365485
Carcinogenesis. 1999 Oct;20(10):1985-95
10506115
Neoplasia. 2001 Jul-Aug;3(4):287-303
11571629
J Biol Chem. 1999 Aug 20;274(34):23679-82
10446122
J Biol Chem. 1996 Dec 27;271(52):33157-60
8969167
Trends Genet. 2002 May;18(5):S1-5
12047956
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10350-5
11504910
Biochem Biophys Res Commun. 1997 Jun 18;235(2):418-23
9199209
J Natl Cancer Inst. 1968 Jan;40(1):43-68
5635018
J Biol Chem. 2002 Oct 25;277(43):40549-56
12189136
J Biol Chem. 2002 May 3;277(18):16189-201
11839751
Carcinogenesis. 2001 Nov;22(11):1765-73
11698337
Endocr Rev. 1999 Feb;20(1):22-45
10047972
Am J Clin Nutr. 1998 Jul;68(1):142-53
9665108
Cancer Res. 1999 Jan 15;59(2):360-6
9927047
Cancer Res. 2000 Apr 15;60(8):2203-8
10786685