Carcinogenesis Advance Access originally published online on June 9, 2008
Carcinogenesis 2008 29(7):1407-1414; 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
First Department of Medicine–ZAFES, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
1 Institute of Pharmaceutical Chemistry–ZAFES, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
* To whom correspondence should be addressed. Division of Gastroenterology, First Department of Medicine–ZAFES, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany. Tel: +49 69 6301 5324; Fax: +49 69 6301 6246; Email: 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 peroxisome proliferator-activated receptor 
(PPAR) in mesalazine's anticarcinogenic 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 poly(ADP-ribose) polymerase (PARP), caspase-8 and caspase-9, as well as on expression of survivin, X-linked inhibitor of apoptosis (Xiap), phosphatase and tensin homolog deleted from chromosome ten (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, whereas the expressions of Xiap, survivin and c-Myc were 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, whereas 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.
Abbreviations: 5-ASA, 5-aminosalicylate; CRC, colorectal cancer; G418, Geneticin 418 sulphate; IAP, inhibitor of apoptosis protein; IBD, inflammatory bowel disease; NSAID, non-steroidal anti-inflammatory drug; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; PPAR, peroxisome proliferator-activated receptor ; PTEN, phosphatase and tension homolog deleted from chromosome ten; UC, ulcerative colitis; Xiap, X-linked inhibitor of apoptosis
Received January 3, 2008; revised May 6, 2008; accepted May 6, 2008.
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