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 inhibitormediated 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. (Cancer Res 2006; 66(14): 7059-66)

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

“…PGE 2 is the prostaglandin that is abundantly present in HCC. Studies have established the important role of the PGE 2 synthesis pathway as a potential target for the treatment and/ or prevention of HCC [8,9] . PGE 2 exerts its biological activities primarily via G-protein-coupled prostaglandin receptors (EP [1][2][3][4] ), which belong to the highly conserved superfamily of www.nature.com/aps Jin J et al Acta Pharmacologica Sinica npg 7-transmembrane-spanning proteins.…”

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

“…In this regard, we and others demonstrated that partial hepatectomy 7 induced COX-2 in hepatocytes and contributed to the progression of cell cycle after partial hepatectomy. 8,9 In addition to liver regeneration after partial hepatectomy or hepatotoxic agents, expression of COX-2 has been detected in animal models of cirrhosis, 10 in human hepatoma cell lines, 11,12 after hepatitis B virus and hepatitis C virus infection, 13,14 and in human HCC. 15 High levels of COX-2-derived prostaglandin E 2 (PGE 2 ) lead to a decrease in apoptosis, a modulation of the immune system and a stimulation of cell migration, proliferation, and angiogenesis.…”

Induction of cell growth arrest and apoptotic cell death in human breast cancer MCF-7 cells by the COX-1 inhibitor FR122047

“…FR122047, a COX-1 inhibitor induced apoptosis in MCF-7 breast cancer cells by a mechanism independent of its ability to suppress PGs synthesis because exogenous PGE 2 had no effect on FR122047-induced apoptosis in MCF-7 cells (data not shown). Celecoxib and other NSAIDs showed that drug-induced apoptosis could be caused through intrinsic pathway by cytochrome c release from mitochondria and activation of caspase-9 as well as extrinsic pathway by activation of caspase-8 (34)(35)(36). FR122047-treated MCF-7 cells exhibited a rapid down-regulation of Bcl-2, resulting in an increase in the Bax/Bcl-2 ratio.…”