TY - JOUR
T1 - COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells
AU - Nzeako, Ugochukwu C.
AU - Guicciardi, Maria Eugenia
AU - Yoon, Jung Hwan
AU - Bronk, Steven F.
AU - Gores, Gregory J.
N1 - Funding Information:
Abbreviations: COX-2, cyclooxygenase-2; TNF, tumor necrosis factor; DR, death receptor; TRAIL, tumor necrosis factor–related apoptosis inducing ligand; DMEM, Dulbecco’s modifed Eagle medium; IL, interleukin; IFN, interferon; IAP, inhibitor of apoptosis proteins; GFP, green fluorescent protein; DAPI, 49,6-diamidino-2-phenylindole dihydrochloride; PCR, polymerase chain reaction. From the Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, MN. Received November 1, 2001; accepted December 7, 2001. Supported by grants from the National Institute of Health DK 59427 (G.J.G.), the Palumbo Foundation, and the Mayo Foundation, Rochester, MN. Presented in part at Digestive Disease Week in Atlanta, GA, May, 2001 and published in abstract form (Gastroenterology 2001;120:A26). Address reprint requests to: Gregory J. Gores, M.D., Professor of Medicine, Mayo Medical School, Clinic, and Foundation, 200 First Street SW, Rochester, MN 55905. E-mail: gores.gregory@mayo.edu; fax: 507-284 0762. Copyright © 2002 by the American Association for the Study of Liver Diseases. 0270-9139/02/3503-0008$35.00/0 doi:10.1053/jhep.2002.31774
PY - 2002
Y1 - 2002
N2 - 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 receptor-mediated 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-α, 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.
AB - 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 receptor-mediated 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-α, 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.
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U2 - 10.1053/jhep.2002.31774
DO - 10.1053/jhep.2002.31774
M3 - Article
C2 - 11870367
AN - SCOPUS:0036191920
VL - 35
SP - 552
EP - 559
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 3
ER -