Carcinogenesis Advance Access published online on June 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn118
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PPAR
is involved in mesalazine-mediated induction of apoptosis and inhibition of cell growth in colon cancer cells
1 First Department of Medicine-ZAFES, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
2 Institute of Pharmaceutical Chemistry-ZAFES, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany
* Address correspondence to: Markus Schwab, Pharmacist, First Department of Medicine, Division of Gastroenterology, ZAFES, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany, Tel: +49-69-6301-5324; Fax: +49-69-6301-6246; E-Mail: M.Schwab{at}med.uni-frankfurt.de
Purpose: Mesalazine has been identified as a candidate chemopreventive agent in colon cancer prophylaxis because of its pro-apoptotic and anti-proliferative effects. However, the precise mechanisms of action are not entirely understood. The aim of our study was to investigate the involvement of PPAR
in mesalazine's anti-carcinogenic actions in colorectal cancer cells. Experimental design: The effects of mesalazine on cell cycle distribution, cell count, proliferation and caspase-mediated apoptosis were examined in Caco-2, HT-29 and HCT-116 cells used as wild-type, dominant-negative PPAR mutant and empty-vector cultures. We focused on caspase-3 activity, cleavage of PARP, caspase-8, and caspase-9, as well as on expression of survivin, Xiap, PTEN and c-Myc. Techniques employed included transfection assays, immunoblotting, flow cytometry analysis, colorimetric and fluorometric assays. Results: Mesalazine caused a time- and dose-dependent decrease in both cell growth and proliferation. Growth inhibition was accompanied by a G1/G0 arrest, a significant increase in PTEN, caspase-3 activity, cleavage of PARP and caspase-8; while the expression of Xiap, survivin and c-Myc was decreased simultaneously. Cleavage of caspase-9 was not observed. Moreover, PPAR expression and activity were elevated. The growth-inhibitory effect of mesalazine was partially reduced in dominant-negative PPAR mutant cells, while the expression of c-Myc was not affected. Mesalazine-mediated increased caspase-3 activity, the expression of PTEN, cleavage of PARP and caspase-8 as well as reduced levels of survivin and Xiap were completely abolished in the PPAR mutant cell lines. Conclusion: This study clearly demonstrates that mesalazine-mediated pro-apoptotic and anti-proliferative actions are regulated via PPAR-dependent and -independent pathways in colonocytes.
Key Words: Colorectal cancer • apoptosis • mesalazine • caspase • PPAR
Received January 3, 2008; revised May 6, 2008; accepted May 6, 2008.
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