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¹ Department of Medicine, University of Colorado Health Sciences Center, Denver, CO; ² University of Colorado Cancer Center, Denver, CO; ³ Department of Veterans Affairs Medical Center, Denver, CO; ⁴ Division of Gastroenterology, University of Utah, Salt Lake City, UT; and ⁵ Institute for Drug Development, San Antonio, TX

Requests for reprints: Pamela L. Rice, Department of Medicine, A009-151, School of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262. Phone: (303) 399-8020 ext. 3629; Fax: (303) 393-5145. E-mail: pamela.rice{at}uchsc.edu

Colorectal cancer (CRC) is the second leading cause of cancer death in the USA. Accumulation of ß-catenin protein is nearly ubiquitous in colon adenomas and cancers, presumably due to mutations in the APC or ß-catenin genes that inhibit proteasome-dependent degradation of ß-catenin protein. Substantial clinical, epidemiological, and animal evidence indicate that sulindac and other non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of CRC. The mechanisms by which sulindac exerts its potent growth inhibitory effects against colon tumor cells are incompletely understood, but down-regulation of ß-catenin has been suggested as one potential mechanism. The goal of this study was to determine the mechanism of ß-catenin protein down-regulation by sulindac metabolites. Treatment of human colon cancer cell lines with apoptotic concentrations of sulindac metabolites (sulindac sulfide, sulindac sulfone) induced a dose- and time-dependent inhibition of ß-catenin protein expression. Inhibition of proteasome activity with MG-132 partially blocked the ability of sulindac sulfide and sulindac sulfone to inhibit ß-catenin protein expression. Pretreatment with the caspase inhibitor z-VAD-fmk blocked morphological signs of apoptosis as well as caspase cleavage, and also partially prevented ß-catenin degradation by sulindac metabolites. These effects occurred in cells with bi-allelic APC mutation (SW480), with wild-type APC but mono-allelic ß-catenin mutation (HCT116) and in cells that lack expression of either COX-1 or -2 (HCT15). These results indicate that loss of ß-catenin protein induced by sulindac metabolites is COX independent and at least partially due to reactivation of ß-catenin proteasome degradation and partially a result of caspase activation during the process of apoptosis.

Grant support: Cancer Research Foundation of America (P.L.R.); University of Colorado Cancer Center (P.L.R., H.S.); and Department of Veterans Affairs Merit Review and REAP Programs.

Received 3/14/03; revised 6/18/03; accepted 6/19/03.

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