TLR-4 Signalling Accelerates Colon Cancer Cell Adhesion via NF-κB Mediated Transcriptional Up-Regulation of Nox-1
Open Access
- 11 October 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (10), e44176
- https://doi.org/10.1371/journal.pone.0044176
Abstract
Surgery induced inflammation is a potent promoter of tumour recurrence and metastasis in colorectal cancer. The recently discovered family of Nox enzymes represent a major source of endogenous reactive oxygen species (ROS) and are now heavily implicated in tumour cell metastasis. Interestingly, Nox enzymes can be ‘purposefully’ activated by inflammatory cytokines and growth factors which are present in abundance in the peri-operative window. As colon cancer cells express Nox enzymes and Toll-like receptor 4 (TLR-4), we hypothesised that LPS may potentiate the ability of colon cancer cells to metastasise via Nox enzyme mediated redox signalling. In support of this hypothesis, this paper demonstrates that LPS induces a significant, transient increase of endogenous ROS in SW480, SW620 and CT-26 colon cancer cells. This increase in LPS-induced ROS activity is completely abrogated by a Nox inhibitor, diphenyleneiodonium (DPI), Nox1 siRNA and an NF-κB inhibitor, Dihydrochloride. A significant increase in Nox1 and Nox2 protein expression occurs following LPS treatment. Inhibition of NF-κB also attenuates the increase of Nox1 and Nox2 protein expression. The sub-cellular location of LPS-induced ROS generation lies mainly in the endoplasmic reticulum. LPS activates the PI3K/Akt pathway via Nox generated ROS and this signal is inhibited by DPI. This LPS activated Nox mechanism facilitates a significant increase in SW480 colon cancer cell adhesion to collagen I, which is inhibited by DPI, Nox1 siRNA and a PI3K inhibitor. Altogether, these data suggest that the LPS-Nox1 redox signalling axis plays a crucial role in facilitation of colon cancer cell adhesion, thus increasing the metastatic potential of colon cancer cells. Nox1 may represent a valuable target in which to prevent colon cancer metastasis.Keywords
This publication has 34 references indexed in Scilit:
- LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signallingJournal of Inflammation, 2012
- Crosstalk between platelet-derived growth factor-induced Nox4 activation and MUC8 gene overexpression in human airway epithelial cellsFree Radical Biology & Medicine, 2011
- Increased Local Recurrence and Reduced Survival From Colorectal Cancer Following Anastomotic LeakAnnals of Surgery, 2011
- BLT2 promotes the invasion and metastasis of aggressive bladder cancer cells through a reactive oxygen species-linked pathwayFree Radical Biology & Medicine, 2010
- Lipopolysaccharide promotes adhesion and invasion of hepatoma cell lines HepG2 and HepG2.2.15Molecular Biology Reports, 2009
- Tumor necrosis factor α activates transcription of the NADPH oxidase organizer 1 (NOXO1) gene and upregulates superoxide production in colon epithelial cellsFree Radical Biology & Medicine, 2008
- NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expressionOncogene, 2008
- Nuclear factor-κB in cancer development and progressionNature, 2006
- The Targeting of Phosphoinositide-3 Kinase Attenuates Pulmonary Metastatic Tumor Growth Following LaparotomyAnnals of Surgery, 2006
- Cutting Edge: Direct Interaction of TLR4 with NAD(P)H Oxidase 4 Isozyme Is Essential for Lipopolysaccharide-Induced Production of Reactive Oxygen Species and Activation of NF-κBPublished by The American Association of Immunologists ,2004