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Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

Oncogene volume 25, pages 1225–1241 (2006)Cite this article

Abstract

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta (PPAR-b/d) overexpression suppresses the activity of PPAR-gamma (PPAR-g) and PPAR-alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-b/d-null cells, and it is not known whether an interaction between PPAR-b/d and PPAR-g exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-b/d. We tested (a) whether PPAR-b/d expression modulates PPAR-g activity in experimental models of the loss and gain of PPAR-b/d function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-b/d and PPAR-g. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-g activity, (b) PPAR-b/d expression suppressed PPAR-g activity in models of both loss and gain of PPAR-b/d function, (c) 15-LOX-1 activated PPAR-g by downregulating PPAR-b/d, and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-b/d suppression of PPAR-g. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-b/d and PPAR-g.

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Acknowledgements

We thank Dr Reuben Lotan for his critical review of the manuscript and helpful comments. We also thank Karen Phillips from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editing the manuscript. In addition, we acknowledge the technical assistance of Dongning Chen. This work was supported in part by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services R01 Grant CA104278 (to IS); the American Cancer Society Scholar Award RSG-04-020-01-CNE (to IS); National Institute of Environmental Health Sciences, NIH Center Grant ES07784; and funding from The Jerry and Maury Rubenstein Foundation.

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Authors and Affiliations

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

    X Zuo, Y Wu, S M Lippman & I Shureiqi

  2. Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J S Morris

  3. Department of Screening and Compound Profiling, GlaxoSmithKline Inc., Research Triangle Park, NC, USA

    J B Stimmel & L M Leesnitzer

  4. Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA

    S M Fischer

  5. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    I Shureiqi

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  1. X Zuo
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Correspondence to I Shureiqi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Zuo, X., Wu, Y., Morris, J. et al. Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene 25, 1225–1241 (2006). https://doi.org/10.1038/sj.onc.1209160

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  • DOI: https://doi.org/10.1038/sj.onc.1209160

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