Hepatitis C virus stimulates the expression of cyclooxygenase-2 via oxidative stress: role of prostaglandin E2 in RNA replication.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Recently, the activation of cyclooxygenase-2 (Cox-2) has been implicated in the HCV-associated hepatocellular carcinoma. In this study, we focus on the signaling pathway leading to Cox-2 activation induced by HCV gene expression. Here, we demonstrate that the HCV-induced reactive oxygen species and subsequent activation of NF-kappaB mediate the activation of Cox-2. The HCV-induced Cox-2 was sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca(2+) chelator (BAPTA-AM), and calpain inhibitor (N-acetyl-Leu-Leu-Met-H). The levels of prostaglandin E(2) (PGE(2)), the product of Cox-2 activity, are increased in HCV-expressing cells. Furthermore, HCV-expressing cells treated with the inhibitors of Cox-2 (celecoxib and NS-398) showed significant reduction in PGE(2) levels. We also observed the enhanced phosphorylation of Akt and its downstream substrates glycogen synthase kinase-3beta and proapoptotic Bad in the HCV replicon-expressing cells. These phosphorylation events were sensitive to inhibitors of Cox-2 (celecoxib and NS-398) and phosphatidylinositol 3-kinase (LY294002). Our results also suggest a potential role of Cox-2 and PGE(2) in HCV RNA replication. These studies provide insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with viral infection.
Waris
Gulam
G
Department of Microbiology, University of Colorado Health Sciences Center, 80262, USA.
Siddiqui
Aleem
A
D000068579:Celecoxib; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology*; D006023:Glycoproteins / Q000494:pharmacology; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D009578:Nitrobenzenes / Q000494:pharmacology; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012093:Replicon; D013449:Sulfonamides / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology
D002614:Chelating Agents; D006023:Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009578:Nitrobenzenes; D011720:Pyrazoles; D011759:Pyrrolidines; D012367:RNA, Viral; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013859:Thiocarbamates; C039304:calpain inhibitors; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C020972:pyrrolidine dithiocarbamic acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases; D000068579:Celecoxib; D015232:Dinoprostone