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YC-1-Induced Cyclooxygenase-2 Expression Is Mediated by cGMP-Dependent Activations of Ras, Phosphoinositide-3-OH-kinase, Akt, and Nuclear Factor-B in Human Pulmonary Epithelial Cells

Graduate Institute of Medical Sciences (M.-S.C., W.-S.L., J.-R.S.), School of Respiratory Therapy (B.-C.C., C.-H.L.), and Graduate Institute of Biomedical Technology (C.-H.L.), College of Medicine, Taipei Medical University, Taipei, Taiwan

We demonstrated previously that 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), an activator of soluble guanylate cyclase (sGC), induces cyclooxygenase-2 (COX-2) expression via cGMP- and p44/42 mitogen-activated protein kinase-dependent pathways in human pulmonary epithelial A549 cells. In this study, we explore the role of Ras, phosphoinositide-3-OH-kinase (PI3K), Akt, and transcription factor nuclear factor-B (NF-B) in YC-1–induced COX-2 expression in A549 cells. A Ras inhibitor (manumycin A), a PI3K inhibitor (wortmannin), an Akt inhibitor (1L-6-Hydroxymethyl-chiro-inositol2-[(R)-2-O-methyl-3-O-octadecylcarbonate]), and an NF-B inhibitor [pyrrolidine dithiocarbamate (PDTC)] all reduced YC-1–induced COX-2 expression. The YC-1–induced increase in COX activity was also blocked by manumycin A, wortmannin, PDTC, and the dominant-negative mutants for Ras (RasN17), Akt (Akt DN), and IB (IBM). The YC-1–induced increase in Ras activity was inhibited by an sGC inhibitor [1H-(1,2,4)oxadiazolo[4,3-a]quinozalin-1-one (ODQ)], a protein kinase G (PKG) inhibitor [1-oxo-9.12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823)], and manumycin A. YC-1–induced Akt activation was also inhibited by ODQ, KT-5823, manumycin A, and wortmannin. YC-1 caused the formation of an NF-B–specific DNA-protein complex and an increase in B-luciferase activity. YC-1–induced B-luciferase activity was inhibited by ODQ, KT-5823, manumycin A, wortmannin, an Akt inhibitor, PDTC, RasN17, Akt DN, and IBM. Likewise, YC-1–induced IKK/ activation was inhibited by ODQ, KT-5823, manumycin A, wortmannin, and an Akt inhibitor. Furthermore, YC-1–induced COX-2 promoter activity was inhibited by manumycin A, RasN17, Akt DN, PDTC, and IBM. Taken together, these results indicate that YC-1 might activate the sGC/cGMP/PKG pathway to induce Ras and PI3K/Akt activation, which in turn initiates IKK/ and NF-B activation and finally induces COX-2 expression in A549 cells.

Address correspondence to: Dr. Chien-Huang, Lin, School of Respiratory Therapy, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. E-mail: chlin{at}tmu.edu.tw

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