Nzeako Ugochukwu C, Guicciardi Maria Eugenia, Yoon Jung-Hwan, Bronk Steven F, Gores Gregory J
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Hepatology. 2002 Mar;35(3):552-9. doi: 10.1053/jhep.2002.31774.
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-alpha, 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.
Fas表达已被证明对异种移植中胆管癌细胞的进展具有负调控作用。然而，许多人类胆管癌表达Fas，这表明这些癌症已形成抑制Fas介导的细胞凋亡的机制。生成前列腺素的环氧合酶-2（COX-2）在许多胆管癌中表达。因此，我们的目的是确定COX-2表达是否抑制胆管癌细胞系KMBC细胞中死亡受体介导的细胞凋亡。这些细胞表达死亡受体Fas、肿瘤坏死因子受体1（TNF-R1）、死亡受体4（DR4）和DR5的信使RNA。这些死亡受体的激动剂CH-11、TNF-α和TRAIL均诱导细胞凋亡。然而，COX-2无论是由促炎细胞因子诱导还是通过瞬时转染，都仅显著抑制Fas介导的细胞凋亡。COX-2抑制剂NS-398可恢复COX-2转染细胞中Fas介导的细胞凋亡。用Fas激动剂CH-11处理后，前列腺素E2可减少细胞凋亡和线粒体去极化。在检测的多种抗凋亡蛋白中，COX-2/前列腺素E2仅增加了Bcl-2家族抗凋亡成员Mcl-1的表达。总之，这些数据表明COX-2生成前列腺素可能通过上调Mcl-1表达特异性抑制Fas介导的细胞凋亡。COX-2的药理抑制可能有助于增强胆管癌细胞中Fas介导的细胞凋亡。
