Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis

• Published in: International journal of biological sciences Vol. 16; no. 8; pp. 1288 - 1301
• Main Authors: Rajamanickam, Vinothkumar, Yan, Tao, Xu, Shanmei, Hui, Junguo, Xu, Xiaohong, Ren, Luqing, Liu, Zhoudi, Liang, Guang, Wang, Ouchen, Wang, Yi
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2020; Ivyspring International Publisher
• Subjects: Activation; Adult; Aged; Aged, 80 and over; Antibodies; Azoxymethane; Blotting, Western; Cancer; Cancer therapies; Cell adhesion; Cell differentiation; Cell Line, Tumor; Cell Survival - drug effects; Chalcones - pharmacology; Colitis; Colon; Colon cancer; Colonic Neoplasms - complications; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colorectal cancer; Cytokines; Dextran; Dextran sulfate; Dextrans; Drinking water; Enzyme-Linked Immunosorbent Assay; Experiments; Gene Silencing; Humans; Immunoprecipitation; Inflammation; Inflammatory bowel disease; Inhibitors; Laboratories; Lipopolysaccharides; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lungs; Lymphocyte Antigen 96 - antagonists & inhibitors; Lymphocyte Antigen 96 - metabolism; Male; Medical research; Metastases; Metastasis; Microorganisms; Middle Aged; Neoplasm Metastasis - prevention & control; NF-κB protein; Penicillin; Real-Time Polymerase Chain Reaction; Receptors; Research Paper; Signal Transduction - drug effects; Signaling; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Tumors; Beijing China; United States > US; China; Japan; NF-κB; MD2; colitis-induced colon cancer; TLR4; colon cancer
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.39098

Toll-like receptor (TLR) signaling is an emerging pathway in tumor cell invasion and metastasis. Myeloid differentiation protein-2 (MD2) contributes to ligand recognition and activation of TLRs in response to exogenous microbial insults or endogenous agents. We hypothesized that blocking MD2 using a specific inhibitor would prevent TLR4-mediated inflammatory responses and metastatic cancer growth. Here, we report that a MD2 inhibitor, L6H21, inhibited migration and invasion of LPS-activated colon cancer CT26.WT cells. These activities were accompanied by inhibition of nuclear factor-κB (NF-κB) activation, and thereby inhibition of the production of pro-inflammatory cytokines and adhesive molecules in colon cancer cells. Furthermore, L6H21 inhibited CT26.WT metastasis to the lung in BALB/c mice as well as suppressed colitis-induced colon cancer induced by azoxymethane/dextran sulfate sodium (AOM/DSS). Taken together, our results demonstrated that L6H21 suppressed tumor invasion and metastasis through blocking TLR4-MD2/NF-κB signaling axis. These findings reveal that inhibition of MD2 may be an important target for the development of colon cancer therapies.