Cyclooxygenase-2 (COX-2) is directly involved but not decisive in proliferation of human hepatocellular carcinoma cells.
Expression of cyclooxygenase-2 (COX-2) is involved in the chronic inflammation-related development of hepatocellular carcinoma (HCC), and the use of selective COX-2 inhibitors might provide new chemoprevention strategies for HCC. However, the role of the COX-2 in hepatocarcinogenesis remains obscure, particularly as it has been primarily studied with selective COX-2 inhibitors that may affect other cellular proteins involved in cell proliferation. Therefore, we investigated the effects of the inhibition of COX-2 by the selective COX-2 inhibitor NS-398 as well as by COX-2 specific small interfering RNA (siRNA) in the human HCC cell lines Hep3B and SNU-387. These cell lines expressed COX-2, and NS-398 induced apoptosis of these cells. NS-398 inhibited more than 60% of prostaglandin E(2) (PGE2) production and cell proliferation in a concentration-dependent manner in these cells. The inhibition of proliferation was almost restored with PGE2 supplement, suggesting that NS-398 may inhibit cell growth partially through inhibition of COX-2 and PGE2 production in human HCC cells. However, treatment with NS-398 led to increased expression of COX-2 in Hep3B and SNU-387 cells. To examine the effect of COX-2 depletion on these cells, we electroporated COX-2-specific siRNAs into SNU-387 cells. We observed significant, sequence-specific reductions in COX-2 expression, PGE2 production, and cell proliferation, though the reduction in cell proliferation was less than that induced by NS-398. In conclusion, these data suggest that COX-2 itself is directly involved, though not decisively, in proliferation of human HCC cells. RNA interference may provide a useful tool for manipulating COX-2-related hepatocarcinogenesis in research and therapeutic settings.
Park
Joong-Won
JW
Research Institute, National Cancer Center, Goyang, Korea. jwpark@ncc.re.kr
Park
Jung Eun
JE
Lee
Jung Ahn
JA
Lee
Chang-Woo
CW
Kim
Chang-Min
CM
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018274:Electroporation; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D034741:RNA, Small Interfering; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection
D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D034741:RNA, Small Interfering; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone