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[Cancer Research 66, 7348-7354, July 15, 2006]
© 2006 American Association for Cancer Research

Clinical Research

Peroxisome Proliferator–Activated Receptor {gamma} as a Molecular Target of Resveratrol-Induced Modulation of Polyamine Metabolism

Sandra Ulrich1, Stefan M. Loitsch1, Oliver Rau2, Andreas von Knethen3, Bernhard Brüne3, Manfred Schubert-Zsilavecz2 and Jürgen M. Stein1

1 First Department of Internal Medicine-ZAFES; 2 Institute of Pharmaceutical Chemistry ZAFES; and 3 Institute of Biochemistry I ZAFES, Johann Wolfgang Goethe University, Frankfurt am Main, Germany

Requests for reprints: Jürgen Stein, FEBG, First Department of Internal Medicine-ZAFES, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Phone: 49-69-6301-5917; Fax: 49-69-6301-83112; E-mail: j.stein{at}em.uni-frankfurt.de.

Previous results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator–activated receptor {gamma} (PPAR{gamma}). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay. PPAR{gamma} ligand–dependent transcriptional activity was measured by a luciferase assay. A dominant-negative PPAR{gamma} mutant was transfected in Caco-2 cells to suppress PPAR{gamma}-mediated functions. Resveratrol inhibits cell growth of both Caco-2 and HCT-116 cells in a dose- and time-dependent manner (P < 0.001). In contrast to Caco-2-wild type cells (P < 0.05), resveratrol failed to increase SSAT activity in dominant-negative PPAR{gamma} cells. PPAR{gamma} involvement was further confirmed via ligand-dependent activation (P < 0.01) as well as by induction of cytokeratin 20 (P < 0.001) after resveratrol treatment. Coincubation with SB203580 abolished SSAT activation significantly in Caco-2 (P < 0.05) and HCT-116 (P < 0.01) cells. The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines. Resveratrol further increased the expression of PPAR{gamma} coactivator PGC-1{alpha} (P < 0.05) as well as SIRT1 (P < 0.01) in a dose-dependent manner after 24 hours of incubation. Based on our findings, p38 MAPK and transcription factor PPAR{gamma} can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer. (Cancer Res 2006; 66(14): 7348-54)




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