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¹ Divisions of Gastroenterology/Hepatology and Oncology, Mayo Clinic, Rochester, Minnesota and ² Department of Gastrointestinal Medicine and Nutrition, University of Texas, M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Frank A. Sinicrope, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail: sinicrope.frank{at}mayo.edu

The nonsteroidal anti-inflammatory drug (NSAID) sulindac prevents experimental colon cancer and can regress precancerous polyps in humans. Sulindac sulfide inhibits cyclooxygenase (COX)-mediated prostaglandin synthesis and retards the growth of cultured colon cell lines primarily by inducing apoptosis. Given the known role of mitogen-activated protein kinase (MAPK) in signal transduction and the regulation of cell survival and death, we determined the effect of sulindac sulfide on MAPK activation, COX-2 expression, and apoptosis induction in HCA-7 human colon cancer cells. Sulindac sulfide treatment was associated with activation of ERK^p44/42 and p38 MAPK in a dosage- and time-dependent manner, and also activated upstream MEK. Similar results were seen in HCT-15 cells and also with the selective COX-2 inhibitor NS398. ERK^p44/42 and p38 activation were accompanied by an induction of COX-2 protein expression. Selective inhibitors of sulindac sulfide–induced ERK^p44/42 (PD98059) and p38 MAPK (SB203580) activation also suppressed the induction of COX-2 by this NSAID. Furthermore, both MAPK inhibitors significantly augmented sulindac sulfide–induced apoptosis, as did suppression of constitutive COX-2 using antisense oligonucleotides. In conclusion, MEK/ERK and p38 MAPK activation mediate COX-2 induction by sulindac sulfide. Selective inhibitors of these MAPKs potentiate apoptosis induction by this NSAID, suggesting a novel strategy for the prevention or treatment of colorectal cancer.

Key Words: mitogen-activated protein (MAP) kinases • NSAIDs • sulindac • apoptosis • cyclooxygenase-2 (COX-2) • colorectal neoplasms

Grant support: National Colorectal Cancer Alliance and NIH RO1 grant DK56378.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with U.S.C. Section 1734 solely to indicate this fact.

³ M. Bertagnolli, unpublished data

Received 8/25/04; revised 11/ 4/04; accepted 11/16/04.