title: IL-1 beta induces urokinase-plasminogen activator expression and cell migration through PKC alpha, JNK1/2, and NF-kappaB in A549 cells.
abstract: Breakdown of the extracellular matrix (ECM) is accomplished by the concerted action of several proteases, including the urokinase plasminogen-activator (uPA) system and matrix metalloproteinases (MMPs), which is crucial for cancer invasion and metastasis. Several reports have shown that the levels of IL-1 beta and MMPs in plasma of the patients with lung cancer are significantly elevated and link to the invasion of tumor cells. Therefore, we investigated whether IL-1 beta-induced expression of uPA participated in lung cancer progression. In this study, IL-1 beta significantly induced uPA expression and activity via PKC alpha-dependent JNK1/2 and NIK cascades, linking to IKK alpha/beta activation, p65 translocation and transcription activity, using pharmacological inhibitors and transfection with dominant negative mutants and siRNAs. IL-1 beta-induced uPA protein and mRNA expression in a time- and concentration-dependent manner, which was inhibited by pretreatment with the inhibitors of JNK1/2 (SP600125), PKC (Ro31-8220, Gö6976), or NF-kappaB (helenalin), and transfection with dominant negative mutants of PKC alpha, NIK, and IKK beta, and siRNAs of JNK1/2 and p65. IL-1 beta stimulated PKC alpha translocation to plasma membrane leading to phosphorylation of JNK1/2, which was attenuated by PKC inhibitors and transfection with shRNAs of JNK1/2, but not by helenalin. In addition, IL-1beta stimulated p65 phosphorylation and translocation into nucleus concomitant with I kappaB alpha phosphorylation and I kappaB alpha degradation, which was mediated via activation of PKC alpha-dependent JNK1/2-NIK/IKK beta cascade. These results demonstrated that in A549 cells, activation of p50/p65 heterodimer through sequential activation of PKC alpha-JNK-NIK-IKK beta-NF-kappaB was required for IL-1 beta-induced uPA expression associated with migration of tumor cells.
authors.affiliation: Department of Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Cheng
authors.forename: Hsi-Lung
authors.initials: HL
authors.lastname: Hsieh
authors.forename: Chi-Chin
authors.initials: CC
authors.lastname: Sun
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Shue-Fen
authors.initials: SF
authors.lastname: Luo
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D048056:Mitogen-Activated Protein Kinase 9; D051571:Protein Kinase C-alpha; D048055:Mitogen-Activated Protein Kinase 8; D014568:Urokinase-Type Plasminogen Activator