Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system.
AffiliationDepartment of Academic Surgery, Cork University Hospital and University College Cork, Cork, Ireland. firstname.lastname@example.org
Receptors, Urokinase Plasminogen Activator
Toll-Like Receptor 4
Tumor Cells, Cultured
Urokinase-Type Plasminogen Activator
MetadataShow full item record
CitationBacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system. 2009, 100 (10):1589-602 Br. J. Cancer
JournalBritish journal of cancer
AbstractPerioperative exposure to lipopolysaccharide (LPS) is associated with accelerated metastatic colorectal tumour growth. LPS directly affects cells through Toll-like receptor 4 (TLR-4) and the transcription factor NF-kappaB. The urokinase plasminogen activator (u-PA) system is intimately implicated in tumour cell extracellular matrix (ECM) interactions fundamental to tumour progression. Thus we sought to determine if LPS directly induces accelerated tumour cell ECM adhesion and invasion through activation of the u-PA system and to elucidate the cellular pathways involved. Human colorectal tumour cell lines were stimulated with LPS. u-PA concentration, u-PA activity, active u-PA, surface urokinase plasminogen activator receptor (u-PAR) and TLR-4 expression were assessed by ELISA, colorimetric assay, western blot analysis and flow cytometry respectively. In vitro tumour cell vitronectin adhesion and ECM invasion were analysed by vitronectin adhesion assay and ECM invasion chambers. u-PA and u-PAR function was inhibited with anti u-PA antibodies or the selective u-PA inhibitors amiloride or WXC-340, TLR-4 by TLR-4-blocking antibodies and NF-kappaB by the selective NF-kappaB inhibitor SN-50. LPS upregulates u-PA and u-PAR in a dose-dependent manner, enhancing in vitro tumour cell vitronectin adhesion and ECM invasion by >40% (P<0.01). These effects were ameliorated by u-PA and u-PAR inhibition. LPS activates NF-kappaB through TLR-4. TLR-4 and NF-kappaB inhibition ameliorated LPS-enhanced u-PA and u-PAR expression, tumour cell vitronectin adhesion and ECM invasion. LPS promotes tumour cell ECM adhesion and invasion through activation of the u-PA system in a TLR-4- and NF-kappaB-dependent manner.
- Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, WXC-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases.
- Authors: Killeen SD, Andrews EJ, Wang JH, Wu T, Schmalix W, Muehlenweg B, Redmond HP
- Issue date: 2007 Jan 29
- Urokinase (u-PA) and the u-PA receptor. Modulation of in vitro invasiveness of human bladder cancer cell lines.
- Authors: Hudson MA, McReynold LM
- Issue date: 1999
- Activation of the urokinase plasminogen activator/urokinase plasminogen activator receptor system and redistribution of E-cadherin are associated with hepatocyte growth factor-induced motility of pancreas tumor cells overexpressing Met.
- Authors: Paciucci R, Vilá MR, Adell T, Díaz VM, Torà M, Nakamura T, Real FX
- Issue date: 1998 Jul
- A cleavage-resistant urokinase plasminogen activator receptor exhibits dysregulated cell-surface clearance.
- Authors: Nieves EC, Manchanda N
- Issue date: 2010 Apr 23
- Effect of oxidative stress on the expression of t-PA, u-PA, u-PAR, and PAI-1 in endothelial cells.
- Authors: Oszajca K, Bieniasz M, Brown G, Swiatkowska M, Bartkowiak J, Szemraj J
- Issue date: 2008 Dec