COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells

Abstract

Fas expression has been shown to negatively regulate the progression of cholangiocarcinoma cells in xenografts. However, many human cholangiocarcinomas express Fas, suggesting these cancers have developed mechanisms to inhibit Fas-mediated apoptosis. Cyclooxygenase-2 (COX-2), which generates prostanoids, is expressed by many cholangiocarcinomas. Therefore, our aim was to determine whether COX-2 expression inhibits death receptormediated apoptosis in KMBC cells, a cholangiocarcinoma cell line. These cells express messenger RNA for the death receptors Fas, tumor necrosis factor receptor 1 (TNF-R1), death receptor 4 (DR4), and DR5. Agonists for these death receptors, CH-11, TNF-␣, and TRAIL all induced apoptosis. However, COX-2, whether induced by proinflammatory cytokines or transient transfection, only significantly inhibited Fas-mediated apoptosis. The COX-2 inhibitor NS-398 restored Fas-mediated apoptosis in COX-2 transfected cells. Prostaglandin E2 reduced apoptosis and mitochondrial depolarization after treatment with the Fas agonist CH-11. Of a variety of antiapoptotic proteins examined, COX-2/prostaglandin E2 only increased expression of Mcl-1, an antiapoptotic member of the Bcl-2 family. In conclusion, these data suggest that prostanoid generation by COX-2 specifically inhibits Fas-mediated apoptosis, likely by up-regulating Mcl-1 expression. Pharmacologic inhibition of COX-2 may be useful in augmenting Fas-mediated apoptosis of cholangiocarcinoma cells.

Expression of antiapoptotic and proapoptotic molecules in diabetic retinas

“…32,33 Furthermore, several studies have established a direct role for Cox-2 in rendering cells resistant to apoptosis by upregulating the expression of Mcl-1 through activation of the PI 3-kinase/Akt-dependent pathway. 18,21 In the present study, cytoplasmic immunoreactivity for Cox-2 was observed in retinal ganglion cells, in the retinal pigment epithelial cells, and in the pigmented and nonpigmented layers of the ciliary body epithelium in diabetic and nondiabetic retinas, confirming previous reports. 31,[34][35][36] The expression of the antiapoptotic molecules Akt, Cox-2, and Mcl-1 in retinal ganglion cells may reflect the fact that neurons tend to be maintained for the entire life span of an individual.…”

“…[11][12][13][14][15][16] Several studies showed that Cox-2 functions as a survival factor by protecting cells from apoptosis. [17][18][19][20][21] Overexpression of Mcl-1, a member of the Bcl-2 family, 22 delays apoptosis by a broad array of agents. 18,21,[23][24][25][26] Bad is a proapoptotic member of the Bcl-2 gene family that promotes apoptosis by binding to and inhibiting functions of antiapoptotic proteins Bcl-2 and Bcl-xL.…”

“…[17][18][19][20][21] Overexpression of Mcl-1, a member of the Bcl-2 family, 22 delays apoptosis by a broad array of agents. 18,21,[23][24][25][26] Bad is a proapoptotic member of the Bcl-2 gene family that promotes apoptosis by binding to and inhibiting functions of antiapoptotic proteins Bcl-2 and Bcl-xL. 10,27 Mitochondria play a key role in the control of apoptotic cell death.…”

Cyclooxygenase-2-derived Prostaglandin E2 Promotes Human Cholangiocarcinoma Cell Growth and Invasion through EP1 Receptor-mediated Activation of the Epidermal Growth Factor Receptor and Akt

“…Furthermore, overexpression of COX-2 in cultured cholangiocarcinoma cells enhances PGE 2 production and promotes tumor growth (12). Consistent with these findings, COX-2 inhibits Fas ligand-mediated apoptosis in cholangiocarcinoma cells (13), and treatment with exogenous PGE 2 increases cholangiocarcinoma cell growth and prevents apoptosis (12)(13)(14)(15)(16)(17). Moreover, prostaglandin signaling also mediates cholangiocarcinoma cell growth induced by hepatocyte growth factor and interleukin-6 (15) and subverts mito-inhibition induced by transforming growth factor-␤ (18).…”

Molecular characterisation of canine nonsteroidal anti-inflammatory drug-activated gene (NAG-1)

“…Overexpression of COX-2 is often observed in many types of cancer cells and results in an increase of cell survival (Lin et al, 2001) and metastasis (Tsujii et al, 1997) and a reduction of apoptosis (Nzeako et al, 2002). COX inhibition by NSAIDs at the protein level is likely to be closely related to their anti-tumorigenic effects.…”