This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shappell, S. B. Articles by Matusik, R. J. Search for Related Content PubMed PubMed Citation Articles by Shappell, S. B. Articles by Matusik, R. J.

Elevated Expression of 12/15-Lipoxygenase and Cyclooxygenase-2 in a Transgenic Mouse Model of Prostate Carcinoma¹

Department of Pathology [S. B. S., S. J. O., S. E. H., S. M., R. L. R., V. V., D. S. D., M. F. S.], Vanderbilt Prostate Cancer Center [S. B. S., S. J. O., S. E. H., S. M., R. L. R., M. F. S., R. J. M.], Vanderbilt Ingram Cancer Center [S. B. S., A. R. B., R. J. M.], Department of Urologic Surgery [S. B. S., N. M., T. Z. T., R. J. M.], Department of Pharmacology [M. J., W. E. B., A. R. B.], Cell Biology [R. J. M.], and Cancer Biology [R. J. M.], Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561; Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan 060 [N. M.]; and Center for Experimental Therapeutics, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 [C. D. F.]

Changes in expression of arachidonic acid (AA) metabolizing enzymes are implicated in the development and progression of human prostate carcinoma (Pca). Transgenic mouse models of Pca that progress from high-grade prostatic intraepithelial neoplasia (HGPIN) to invasive and metastatic carcinoma could facilitate study of the regulation and function of these genes in Pca progression. Herein we characterize the AA-metabolizing enzymes in transgenic mice established with a prostate epithelial-specific long probasin promoter and the SV40 large T antigen (LPB-Tag mice) that develop extensive HGPIN and invasive and metastatic carcinoma with neuroendocrine (NE) differentiation. Murine 8-lipoxygenase (8-LOX), homologue of the 15-LOX-2 enzyme that is expressed in benign human prostatic epithelium and reduced in Pca, was not detected in wild-type or LPB-Tag prostates as determined by enzyme assay, reverse transcription-PCR, and immunohistochemistry. The most prominent AA metabolite in mouse prostate was 12-HETE. Wild-type prostate (dorsolateral lobe) converted 1.6 ± 0.5% [¹⁴C]AA to 12-HETE (n = 7), and this increased to 8.0 ± 4.4% conversion in LPB-Tag mice with HGPIN (n = 13). Quantitative real-time reverse transcription-PCR and immunostaining correlated the increased 12-HETE synthesis with increased neoplastic epithelial expression of 12/15-LOX, the leukocyte-type (L) of 12-LOX and the murine homologue of human 15-LOX-1. Immunostaining showed increased L12-LOX in invasive carcinoma and approximately one-half of metastatic foci. COX-2 mRNA was detectable in neoplastic prostates with HGPIN but not in wild-type prostate. By immunostaining, COX-2 was increased in the neoplastic epithelium of HGPIN but was absent in foci of invasion and metastases. We conclude that (a) AA metabolism in wild-type mouse prostate differs from humans in the basal expression of LOXs (15-LOX-2 in human, absence of its 8-LOX homologue in mouse prostate); (b) increased expression of 12/15-LOX in HGPIN and invasive carcinoma of the LPB-Tag model is similar to the increased 15-LOX-1 in high-grade human Pca; and (c) the LPB-Tag model shows increased COX-2 in HGPIN, and therefore, it may allow additional definition of the role of this enzyme in the subset of human HGPINs or other precursor lesions that are COX-2 positive, as well as investigation of its contribution to neoplastic cell proliferation and tumor angiogenesis in Pca.

This article has been cited by other articles:

				S. Y. Cheranov, D. Wang, V. Kundumani-Sridharan, M. Karpurapu, Q. Zhang, K. R. Chava, and G. N. Rao The 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Janus kinase 2-signal transducer and activator of transcription-5B-dependent expression of interleukin-8 Blood, June 4, 2009; 113(23): 6023 - 6033. [Abstract] [Full Text] [PDF]

				T. Zhao, D. Wang, S. Y. Cheranov, M. Karpurapu, K. R. Chava, V. Kundumani-Sridharan, D. A. Johnson, J. S. Penn, and G. N. Rao A novel role for activating transcription factor-2 in 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis J. Lipid Res., March 1, 2009; 50(3): 521 - 533. [Abstract] [Full Text] [PDF]

				Y.-S. Piao, Y.-C. Du, H. Oshima, J.-C. Jin, M. Nomura, T. Yoshimoto, and M. Oshima Platelet-type 12-lipoxygenase accelerates tumor promotion of mouse epidermal cells through enhancement of cloning efficiency Carcinogenesis, February 1, 2008; 29(2): 440 - 447. [Abstract] [Full Text] [PDF]

				B. Zhang, H. Cao, and G. N. Rao Fibroblast Growth Factor-2 Is a Downstream Mediator of Phosphatidylinositol 3-Kinase-Akt Signaling in 14,15-Epoxyeicosatrienoic Acid-induced Angiogenesis J. Biol. Chem., January 13, 2006; 281(2): 905 - 914. [Abstract] [Full Text] [PDF]

				B. Zhang, H. Cao, and G. N. Rao 15(S)-Hydroxyeicosatetraenoic Acid Induces Angiogenesis via Activation of PI3K-Akt-mTOR-S6K1 Signaling Cancer Res., August 15, 2005; 65(16): 7283 - 7291. [Abstract] [Full Text] [PDF]

				J.-G. Jiang, C.-L. Chen, J. W. Card, S. Yang, J.-X. Chen, X.-N. Fu, Y.-G. Ning, X. Xiao, D. C. Zeldin, and D. W. Wang Cytochrome P450 2J2 Promotes the Neoplastic Phenotype of Carcinoma Cells and Is Up-regulated in Human Tumors Cancer Res., June 1, 2005; 65(11): 4707 - 4715. [Abstract] [Full Text] [PDF]

				Y. Zeng, M. Yokohira, K. Saoo, H. Takeuchi, Y. Chen, K. Yamakawa, Y. Matsuda, Y. Kakehi, and K. Imaida Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor Carcinogenesis, June 1, 2005; 26(6): 1109 - 1116. [Abstract] [Full Text] [PDF]

				J. N. Davis, M. T. McCabe, S. W. Hayward, J. M. Park, and M. L. Day Disruption of Rb/E2F Pathway Results in Increased Cyclooxygenase-2 Expression and Activity in Prostate Epithelial Cells Cancer Res., May 1, 2005; 65(9): 3633 - 3642. [Abstract] [Full Text] [PDF]

				K. Gronert, N. Maheshwari, N. Khan, I. R. Hassan, M. Dunn, and M. Laniado Schwartzman A Role for the Mouse 12/15-Lipoxygenase Pathway in Promoting Epithelial Wound Healing and Host Defense J. Biol. Chem., April 15, 2005; 280(15): 15267 - 15278. [Abstract] [Full Text] [PDF]

				Y.N. Ye, W.K.K. Wu, V.Y. Shin, I.C. Bruce, B.C.Y. Wong, and C.H. Cho Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke Carcinogenesis, April 1, 2005; 26(4): 827 - 834. [Abstract] [Full Text] [PDF]

				M. S. Chang, C. Schneider, R. L. Roberts, S. B. Shappell, F. R. Haselton, W. E. Boeglin, and A. R. Brash Detection and Subcellular Localization of Two 15S-Lipoxygenases in Human Cornea Invest. Ophthalmol. Vis. Sci., March 1, 2005; 46(3): 849 - 856. [Abstract] [Full Text] [PDF]

				S. Gupta, V. M. Adhami, M. Subbarayan, G. T. MacLennan, J. S. Lewin, U. O. Hafeli, P. Fu, and H. Mukhtar Suppression of Prostate Carcinogenesis by Dietary Supplementation of Celecoxib in Transgenic Adenocarcinoma of the Mouse Prostate Model Cancer Res., May 1, 2004; 64(9): 3334 - 3343. [Abstract] [Full Text] [PDF]