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- Title
IL-1β induces urokinse-plasminogen activator expression and cell migration through PKCα, JNK1/2, and NF-κB in A549 cells.
- Authors
CHING-YI CHENG; HSI-LUNG HSIEH; CHI-CHIN SUN; CHIH-CHUNG LIN; SHUE-FEN LUO; CHUEN-MAO YANG
- 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-1β 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-1β-induced expression of uPA participated in lung cancer progression. In this study, IL-1β significantly induced uPA expression and activity via PKCα-dependent JNK1/2 and NIK cascades, linking to IKKα/β activation, p65 translocation and transcription activity, using pharmacological inhibitors and transfection with dominant negative mutants and siRNAs. IL-1β-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-κB (helenalin), and transfection with dominant negative mutants of PKCα, NIK, and IKKβ, and siRNAs of JNK1/2 and p65. IL-1β stimulated PKCα 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-1β stimulated p65 phosphorylation and translocation into nucleus concomitant with IκBα phosphorylation and IκBα degradation, which was mediated via activation of PKCα-dependent JNK1/2–NIK/IKKβ cascade. These results demonstrated that in A549 cells, activation of p50/p65 heterodimer through sequential activation of PKCα–JNK–NIK–IKKβ–NF-κB was required for IL-1β-induced uPA expression associated with migration of tumor cells. J. Cell. Physiol. 219: 183–193, 2009. © 2008 Wiley-Liss, Inc.
- Publication
Journal of Cellular Physiology, 2009, Vol 219, Issue 1, p183
- ISSN
0021-9541
- Publication type
Academic Journal
- DOI
10.1002/jcp.21669