title: Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma.
abstract: Inhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX-2 inhibitor-mediated apoptosis. Furthermore, our findings showed a link between COX-2 inhibition and the mitochondrial apoptosis pathway. COX-2 inhibition led to a rapid down-regulation of myeloid cell leukemia-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, followed by translocation of Bax to mitochondria and cytochrome c release from mitochondria. Consequently, overexpression of Mcl-1 led to inhibition of COX-2 inhibitor-mediated apoptosis. Furthermore, blocking endogenous Mcl-1 function using a small-interfering RNA approach enhanced COX-2 inhibitor-mediated apoptosis. It is of clinical importance that celecoxib acted synergistically with chemotherapeutic drugs in the induction of apoptosis in HCC cells. The clinical relevance of these results is further substantiated by the finding that COX-2 inhibitors did not sensitize primary human hepatocytes toward chemotherapy-induced apoptosis. In conclusion, COX-2 inhibition engages different apoptosis pathways in HCC cells stimulating death receptor signaling, activation of caspases, and apoptosis originating from mitochondria.
authors.affiliation: Institute of Pathology and Department of General Surgery, University of Heidelberg, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kern
authors.forename: Anke M
authors.initials: AM
authors.lastname: Haugg
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Koch
authors.forename: Tobias
authors.initials: T
authors.lastname: Schilling
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Binje
authors.initials: B
authors.lastname: Fleischer
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Christoph
authors.initials: C
authors.lastname: Michalski
authors.forename: Henning
authors.initials: H
authors.lastname: Schulze-Bergkamen
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D013449:Sulfonamides; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D019014:fas Receptor; D051546:Cyclooxygenase 2; D000068579:Celecoxib