G1 delay in cells overexpressing prostaglandin endoperoxide synthase-2.

DuBois RN, Shao J, Tsujii M, Sheng H, Beauchamp RD
Cancer Res. 1996 56 (4): 733-7

PMID: 8631005

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.

MeSH Terms (28)

Adenoma Animals Anti-Inflammatory Agents, Non-Steroidal Anticarcinogenic Agents Aspirin Cell Line Colonic Neoplasms Colorectal Neoplasms Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases Cyclin D1 Cyclins DNA Epithelium G1 Phase Humans Intestines Kinetics Oncogene Proteins Open Reading Frames Prostaglandin-Endoperoxide Synthases Proto-Oncogene Proteins Rats Recombinant Proteins Retinoblastoma Protein Time Factors Transfection United States

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