The precise genetic and molecular defects underlying
epithelial ovarian cancer (EOC) remain largely unknown, and treatment options for patients with advanced disease are limited.
Cyclooxygenases (COX-1 and COX-2) catalyze the conversion of
arachidonic acid to
prostaglandins. Whereas overwhelming evidence suggests a role for COX-2 in a variety of
cancers, the contribution of COX-1 remains much less explored. The expression status of COX
isoforms in
ovarian cancers also remains confusing. We have previously shown that human epithelial ovarian
tumors have increased levels of COX-1 but not COX-2. To more carefully examine the role of COXs in
ovarian cancer, we used a mouse model of EOC in which genetic and oncogenic modifications were experimentally engineered into ovarian surface epithelial cells (OSE) thought to be the cells of origin for human EOC. These OSE cells produce
tumors when allografted into host mice. Using multiple approaches, we observed that OSE cells and the
tumors comprised of these cells express high levels of COX-1 but not COX-2.
Prostacyclin (PGI(2)) is the major
prostaglandin generated downstream of COX-1 in these cells, and
SC-560, a COX-1-selective inhibitor, dramatically inhibits PGI(2) production. More importantly,
SC-560 reduced the growth of
tumors when OSE cells were allografted in nude female mice. In contrast, the COX-2-selective inhibitor
celecoxib had little effect on
tumor growth. The growth inhibitory effects of
SC-560 result from reduced cell proliferation and/or accelerated apoptosis. Our results imply COX-1 as a target for the prevention and/or treatment of EOC.