IL-1β induces urokinse-plasminogen activator expression and cell migration through PKCα, JNK1/2, and NF-κB in A549 cells

✍ Scribed by Ching-Yi Cheng; Hsi-Lung Hsieh; Chi-Chin Sun; Chih-Chung Lin; Shue-Fen Luo; Chuen-Mao Yang

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 516 KB
• Volume: 219
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21669

✦ Synopsis

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.