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15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor γ

Oncogene volume 25, pages 6015–6025 (2006)Cite this article

Abstract

An inverse relationship exists between the expression of 15-lipoxygenase-2 (15-LOX-2) and peroxisome proliferator-activated receptor γ (PPARγ) in normal prostate epithelial cells (PrECs) compared with their expression in prostate carcinoma cells (PC-3). The reason for this difference, however, is unknown. We hypothesized that this inverse expression partly involves the 15-LOX-2 promoter and 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), a product of 15-LOX-2 that binds to PPARγ. We identified an active steroid nuclear receptor half-site present in the 15-LOX-2 promoter fragment F-5 (−618/+177) that can interact with PPARγ. After forced expression of wild-type PPARγ, 15-(S)-HETE (1 μ M) decreased F-5 reporter activity in PrECs whereas forced expression of 15-LOX-2 resulted in 15-(S)-HETE production which enhanced F-5 activity in PC-3. In contrast, the expression of dominant-negative PPARγ reversed the transcriptional activation of F-5 by enhancing it 202-fold in PrEC or suppressing it in PC-3; the effect in PC-3 was positively increased 150-fold in the presence of 15-(S)-HETE (1 μ M). Peroxisome proliferator-activated receptor γ interacted with 15-LOX-2 promoter sequences in pulldown experiments using biotinylated 15-LOX-2 (−560/−596 bp) oligonucleotides. In gelshift analyses PPARγ and orphan receptor RORα were shown to interact with the F-5 fragment in PC-3 cells. These data suggest that crosstalk mechanisms exist between the 15-LOX-2 gene and PPARγ to counterbalance expression and help explain the inverse relationship of these genes in normal versus cancer cells.

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Acknowledgements

We thank Dr IC Kilty (Pfizer Global Research and Development, Sandwich, Kent, UK) for providing the 15-LOX-2 expression plasmid, Dr VKK Chatterjee (University of Cambridge, Cambridge, UK) for the dnPPARγ expression plasmid, Dr V Giguere (University of McGill, Canada) for the RORα 1 expression vector and Dr Alex Elbrecht (Merck & Co., Inc. NJ, USA) for the hPPARγ expression plasmids. This work was supported by Grant TPRN-99-240-01-CNE-1 from the American Cancer Society and by National Cancer Institute Grants P01 CA-91844, R21 CA-10241 and R21 CA-102145 and a grant from the Cancer Research and Prevention Foundation. Also supported in part by a National Cancer Institute grant CA-16672-28. We also thank Dr EM McDonald in the Department of Scientific Publications at M. D. Anderson Cancer Center for editorial expertise.

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Authors and Affiliations

  1. Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    V Subbarayan, L C Hsi, A L Sabichi, N Llansa, G Mendoza, S M Lippman & D G Menter

  2. Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    J Kim & C J Logothetis

  3. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P Yang & R A Newman

  4. Department of Eicosanoids and Tumor Development, German Cancer Research Center, Heidelberg, Germany

    P Krieg

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  1. V Subbarayan
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Correspondence to D G Menter.

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Subbarayan, V., Krieg, P., Hsi, L. et al. 15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor γ. Oncogene 25, 6015–6025 (2006). https://doi.org/10.1038/sj.onc.1209617

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