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Carcinogenesis Advance Access published online on May 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn122
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MESALAZINE NEGATIVELY REGULATES CDC25A PROTEIN EXPRESSION AND PROMOTES ACCUMULATION OF COLON CANCER CELLS IN S PHASE

Carmine Stolfi, Daniele Fina, Roberta Caruso, Flavio Caprioli, Massimo Claudio Fantini, Angelamaria Rizzo, Massimiliano Sarra, Francesco Pallone and Giovanni Monteleone

Dipartimento di Medicina Interna, Università Tor Vergata, Rome, Italy

Address for correspondence Giovanni Monteleone, Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1 00133 Rome, Italy Phone +39.06.72596158 Fax +39.06.72596391 Email: Gi.Monteleone{at}Med.uniroma2.it

Regular consumption of mesalazine has been associated with a reduced risk of colorectal cancer (CRC) in patients with inflammatory bowel disease. The molecular mechanisms underlying the anti-neoplastic effect of 5-ASA remain however poorly characterized. In this study we examined whether mesalazine affects cell cycle progression and analyzed specific checkpoint pathways in experimental models of CRC.

Mesalazine inhibited the growth of HCT-116 and HT-29 cells, two CRC cell lines that express either a wild-type or mutated p53. Cell cycle analysis revealed that mesalazine induced cells to accumulate in S-phase. This effect was associated with a sustained phosphorylation of the cyclin-dependent kinases (CDK) 2 at Thr-14 and Tyr-15 residues, an event that inactivates the CDK2–cyclin complex, and blocks S/G2 phase cell cycle transition. Consistently mesalazine reduced the protein content of CDC25A, a phosphatase which regulates CDK2 phosphorylation status. Analysis of up-stream kinases that negatively control CDC25A expression showed that mesalazine enhanced the activation of CHK1 and CHK2. However, silencing of CHK1 and CHK2 did not prevent the mesalazine-induced CDC25A protein down-regulation. By contrast, CDC25A protein ubiquitination and degradation, and accumulation of cells in S-phase following mesalazine exposure were reverted by proteasome inhibitors. Notably, mesalazine also inhibited CDC25A in human CRC explants. Finally, we showed that mesalazine down-regulated CDC25A in CT26, a murine CRC cell line, and prevented the formation of CT26-derived tumours in mice. Data show that mesalazine negatively regulates CDC25A protein expression thus delaying CRC cell progression.

Key Words: mesalazine • 5-Aminosalicylic acid • colon cancer • CDC25A

Received January 4, 2008; revised April 15, 2008; accepted May 15, 2008.


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