Apoptotic Effect of Celecoxib Dependent Upon p53 Status in Human Ovarian Cancer Cells

Abstract

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, induces the apoptosis in various cancers in COX-2 dependent and/or independent manners. The p53 protein is mutated in 50% of all human tumors and plays a key role in apoptosis, cell cycle, and the expression of several proteins. In ovarian cancer, the rate of p53 mutation has been shown to be very high and associated with poor prognosis. To explore the importance of functional status of p53 in apoptosis by celecoxib in ovarian cancer cells, the cellular response to celecoxib was determined in SK-OV3 ovarian cancer cells with null type p53 and PA-1 with wild-type p53. Our results showed that celecoxib inhibited cell growth more in PA-1 than in SK-OV3. The underlying antiproliferative mechanism may differ between these two cell types dependent upon the functional status of p53, which plays integral roles in regulating cell cycle and survival. Higher sub-G1 was shown in PA-1 than in SK-OV3 in response to celecoxib (PA-1 versus SK-OV3; 60.28% versus 6.69%). Caspase -8, -9, and -3 were activated in PA-1 cells, but not in SK-OV3 cells. These results suggest that death receptor and mitochondria-mediated apoptotic pathways may be involved in celecoxib-induced apoptosis dependent upon the functional status of p53. Our article demonstrated that the celecoxib effectively inhibited cell growth and induced apoptosis in human ovarian cancer cells with wild-type p53. Thus, apoptotic effect by celecoxib seemed to be different dependent upon the functional status of p53.

Cyclin D1 Expression and the Inhibitory Effect of Celecoxib on Ovarian Tumor Growth in Vivo

“…Release of cytochrome C was associated with activation of caspase activity, eventually resulting in apoptosis. Celecoxib effectively inhibited cell growth and induced apoptosis in human ovarian cancer cells dependent upon the functional status of p53 [30]. Thus, a clear picture of the exact pathways by which COX-2 inhibitors induce apoptosis has yet to emerge.…”

Use of Nonsteroidal Antiinflammatory Agents and Incidence of Ovarian Cancer in 2 Large Prospective Cohorts

“…NSAIDs are thought to decrease inflammation by inhibiting cyclooxygenases (2)(3)(4)(5), enzymes involved in the synthesis of prostaglandins, which in turn can contribute to carcinogenesis by promoting cellular proliferation and inhibiting apoptosis (6,7). In spite of the accruing experimental evidence implicating cyclooxygenase and its inhibition by NSAIDs in ovarian carcinogenesis (8)(9)(10)(11)(12)(13)(14)(15)(16)(17), epidemiologic studies have been inconsistent (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms

“…Unfortunately, all tested cell lines contain TP53 mutations. This complicates the interpretation of the COX2 inhibitory mechanism, which has been described to be dependent on the p53 functional status at least for celecoxib in vitro [83]. As the functionality of mutated p53 is questionable in BON and LCC-18 cells, p53-independent antiproliferative effects of COX2 inhibition are likely in this context.…”