Journal Article

PPARγ is involved in mesalazine-mediated induction of apoptosis and inhibition of cell growth in colon cancer cells

Markus Schwab, Veerle Reynders, Stefan Loitsch, Yogesh M. Shastri, Dieter Steinhilber, Oliver Schröder and Jürgen Stein

in Carcinogenesis

Volume 29, issue 7, pages 1407-1414
Published in print July 2008 | ISSN: 0143-3334
Published online June 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn118
PPARγ is involved in mesalazine-mediated induction of apoptosis and inhibition of cell growth in colon cancer cells

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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 γ (PPARγ) 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 PPARγ 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, PPARγ expression and activity were elevated. The growth-inhibitory effect of mesalazine was partially reduced in dominant-negative PPARγ 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 PPARγ mutant cell lines. Conclusion: This study clearly demonstrates that mesalazine-mediated pro-apoptotic and anti-proliferative actions are regulated via PPARγ-dependent and -independent pathways in colonocytes.

Journal Article.  5712 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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