Cyclooxygenase-2 Overexpression Inhibits Platelet-derived Growth Factor-induced Mesangial Cell Proliferation through Induction of the Tumor Suppressor Gene p53 and the Cyclin-dependent Kinase Inhibitors p21waf-1/cip-1 and p27kip-1

Abstract

Cyclooxygenase-2 (COX-2) is an inducible enzyme and serves as a source of paracrine prostaglandin E2 (PGE2) formation in many tissues. In glomerular immune injury COX-2 formation is up-regulated in association with increased mesangial cell growth. To examine whether COX-2 exerts growth modulating effects on glomerular cells, we established two separate COX-2-overexpressing mesangial cell lines (COX-2؉) and assessed their proliferative response to the potent mesangial cell growth-promoting factor, platelet-derived growth factor (PDGF). PDGF increased proliferation in mocktransfected cells. In contrast, PDGF did not induce proliferation in COX-2؉ cells. Our results also showed that the tumor suppressor protein p53 and the cyclindependent kinase inhibitors p21 cip-1 and p27 kip-1 were up-regulated in COX-2؉ cells de novo as well as under PDGF-stimulated conditions. To study whether COX-2 products are required for these effects, COX-2؉ cells were treated with indomethacin (1 g/ml) or NS-398 (3 M). Unexpectedly, both COX inhibitors had no significant effect on cell proliferation, not on the protein levels of p53, p21 cip-1 , or p27 kip-1 . To evaluate the role of p21 cip-1 and p27 kip-1 , COX-2 was overexpressed in mesangial cells derived from p21 cip-1 (p21؊/؊ COX-2؉) and p27 kip-1 (p27؊/؊ COX-2؉) null mice. In contrast to the wild type COX-2؉ cells, p21؊/؊ COX-2؉ and p27؊/؊ COX-2؉ cells proliferated in response to PDGF. These data suggest that COX-2 inhibits mesangial cell proliferation by a novel mechanism that is independent of prostaglandin synthesis, but involves p53, p21 cip-1 , and p27 kip-1 .

Gallotannin regulates apoptosis and COX-2 expression via Akt and p38kinase pathway in human lung cancer cell line, A549

“…However, the relationship between COX-2 expression and growth of cancer cells is more complicate than the foregoing results and this is indicated by reports that COX-2 may play pro-apoptotic roles (Zahner et al 2002). Moreover, COX-2 expression by pharmacological reagents leads to inhibition of colon cancer cell growth (Williams et al 2003).…”

Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells

“…Treatment of human glioblastoma and medulloblastoma cells with the nonsteroidal anti-inflammatory drug flurbiprofen has been shown to enhance COX-2 expression, cause complex formation of COX-2 protein with p53, and suppress tumor growth (18). Overexpression of COX-2 inhibits platelet-derived growth factor -induced proliferation via the induction of p53, as well as of p21 (23). On the other hand, studies by Corcoran et al (19) indicate that p53 up-regulates COX-2 and that COX-2 in turn may negatively affect p53 activity through mechanisms that could involve physical interactions between COX-2 and p53.…”

“…However, the nature of the relationship of COX-2 protein to cancer cell growth is more complex than the foregoing evidence infers and this is suggested by reports that COX-2 may be proapoptotic (23,24) and that pharmacologic induction of COX-2 expression results in inhibition of colon cancer cell growth (25). Pharmacologic inhibition of COX-2 activity in colon cancer cells has been shown to increase the nuclear localization of active p53 (26).…”

Cyclooxygenase-2, Epidermal Growth Factor Receptor, and Aromatase Signaling in Inflammation and Mesothelioma

“…In malignant mesothelioma, the cytoplasmic expression of HuR was significantly correlated with high COX-2 expression and with poor survival (34). Finally, COX-2 has been proposed to exert its influence on mesangial cell proliferation in vitro by a novel mechanism involving the tumor suppressor p53 and the cell-cycle inhibitors p21 and p27 (35). Interestingly, several recent studies have investigated the potential prognostic value of p53, p21, and p27 in malignant mesotheliomas.…”