title: Interleukin-1beta-induced iNOS expression in human lung carcinoma A549 cells: involvement of STAT and MAPK pathways.
abstract: For understanding of signaling molecules important in lung cancer growth and progression, IL-1beta effect was analyzed on iNOS expression and key signaling molecules in human lung carcinoma A549 cells and established the role of specific signaling molecules by using specific chemical inhibitors. IL-1beta exposure (10 ng/ml) induced strong iNOS expression in serum starved A549 cells. Detailed molecular analyses showed that IL-1beta increased expression of phosphorylated STAT1 (Tyr701 and Ser727) and STAT3 (Tyr705 and Ser727) both in total cell lysates and nuclear lysates. Further, IL-1beta exposure strongly activated MAPKs (ERK1/2, JNK1/2 and p38) and Akt as well as increased nuclear levels of NF-kappaB and HIF-1alpha in A549 cells. Use of specific chemical inhibitors for JAK1 kinase (piceatannol), JAK2 kinase (AG-490), MEK1/2 (PD98059) and JNK1/2 (SP600125) revealed that IL-1beta-induced iNOS expression involved signaling pathways in addition to JAK-STAT and ERK1/2-JNK1/2 activation. Overall, these results suggested that instead of specific pharmacological inhibitors, use of chemopreventive agents with broad spectrum efficacy to inhibit IL-1beta-induced signaling cascades and iNOS expression would be a better strategy towards lung cancer prevention and/or treatment.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, CO 80045, USA.
authors: Kameswaran
authors: K
authors: Ravichandran
authors: Alpna
authors: A
authors: Tyagi
authors: Gagan
authors: G
authors: Deep
authors: Chapla
authors: C
authors: Agarwal
authors: Rajesh
authors: R
authors: Agarwal
mesh_terms: D002277:Carcinoma / Q000378:metabolism* / Q000517:prevention & control; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053613:Janus Kinase 1 / Q000187:drug effects; D008175:Lung Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D053613:Janus Kinase 1