Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation
Open Access
- 30 August 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 30 (2), 201-211
- https://doi.org/10.1038/onc.2010.401
Abstract
Pancreatic adenocarcinoma upregulated factor (PAUF) is overproduced in certain types of cancer. However, little is known of the tumorigenic function of PAUF. In this study, we report the X-ray crystal structure of PAUF and reveal that PAUF is a mammalian lectin normally found in plant lectins. We also identify PAUF as an endogenous ligand of Toll-like receptor 2 (TLR2) and TLR4 by screening extracellular domain receptor pools. We further confirmed the specificity of the PAUF–TLR2 interaction. PAUF induces extracellular signal-regulated kinase (ERK) phosphorylation and activates the IKK-β-mediated TPL2/MEK/ERK signaling pathway through TLR2. In agreement with the result of TLR2-mediated ERK activation by PAUF, PAUF induces increased expression of the protumorigenic cytokines RANTES and MIF in THP-1 cells. However, PAUF does not fully activate Iκ-B-α signaling pathways in THP-1 cells, and fails to translocate the p65 subunit of the nuclear factor-κB (NF-κB) complex into the nucleus, resulting in no NF-κB activation. Surprisingly, we found that PAUF also associated with the CXC chemokine receptor (CXCR4)–TLR2 complex and inhibited CXCR4-dependent, TLR2-mediated NF-κB activation. Together, these findings suggest that the new cancer-associated ligand, PAUF, may activate TLR-mediated ERK signaling to produce the protumorigenic cytokines, but inhibits TLR-mediated NF-κB signaling, thereby facilitating tumor growth and escape from innate immune surveillance.Keywords
This publication has 36 references indexed in Scilit:
- Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense functionProceedings of the National Academy of Sciences, 2008
- Chemokines in tumor angiogenesis and metastasisCancer and Metastasis Reviews, 2007
- Role of chemokines in tumor growthCancer Letters, 2007
- Cancer CXC chemokine networks and tumour angiogenesisEuropean Journal Of Cancer, 2006
- Toll-like receptor signallingNature Reviews Immunology, 2004
- Structural Basis for the Carbohydrate Specificities of Artocarpin: Variation in the Length of a Loop as a Strategy for Generating Ligand SpecificityJournal of Molecular Biology, 2004
- Cancer Statistics, 2004CA: A Cancer Journal for Clinicians, 2004
- Structural Basis of the Carbohydrate Specificities of Jacalin: An X-ray and Modeling StudyJournal of Molecular Biology, 2003
- Macrophage Migration Inhibitory Factor (MIF)Annals of the New York Academy of Sciences, 2003
- What Is the Evidence That Tumors Are Angiogenesis Dependent?JNCI Journal of the National Cancer Institute, 1990