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G₁ Delay in Cells Overexpressing Prostaglandin Endoperoxide Synthase-2¹

Departments of Medicine [R. N. D., J. S., M. T.], Surgery [H. S., R. D. B.], and Cell Biology [R. N. D., R. D. B.], Vanderbilt University Medical Center, and Veterans Administration Medical Center [R. N. D.], Nashville, Tennessee 37232-2279

Colorectal cancer is the second leading cause of death from cancer in the United States. Continuous use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the risk of colorectal cancer in humans by 40–50%. Patients with familial adenomatous polyposis who take NSAIDs, such as sulindac, undergo a regression of intestinal adenomas. Rodents exposed to carcinogens that cause colon cancer have a 50–60% reduction in the size and number of colonic tumors when treated continuously with NSAIDs. One common target for these drugs is prostaglandin endoperoxide synthase, also referred to as cyclooxygenase (COX). We and others have shown recently that COX-2 levels are increased dramatically in 85–90% of human colorectal adenocarcinomas and in 40–50% of colonic adenomas. We prepared intestinal epithelial cells that express the COX-2 gene permanently and found that they have altered adhesion properties and resist undergoing apoptosis. We report here that these cells also have a 3-fold increase in the duration of G₁, lower levels of cyclin D1 protein, and a marked decrease in retinoblastoma kinase activity associated with cyclin-dependent kinase 4. The delay in G₁ transit may relate to the resistance of these cells to undergo programmed cell death, which could affect their tumorigenic potential.

¹ This work was supported in part from the United States Public Health Services Grants DK-47297-01A1 (R. N. D.), 5P30 ES 00267-29 (R. N. D.), GM-53319-1 (R. D. B.), and CA-69457 (R. D. B.). R. N. D. is a recipient of a Veterans Administration Research Associate Career Development Award and a Boehringer Ingelheim New Investigator Award and is an American Gastroenterological Association Industry Research Scholar.

² To whom requests for reprints should be addressed, at Department of Medicine/GI, MCN C-2104, Vanderbilt University Medical Center, Nashville, TN 37232-2279. Phone: (615) 343-8989; Fax: (615) 343-6229.

Received 12/ 1/95. Accepted 1/ 2/96.

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