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

Abstract:

: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.

journal_name

Int J Biol Sci

authors

Rajamanickam V,Yan T,Xu S,Hui J,Xu X,Ren L,Liu Z,Liang G,Wang O,Wang Y

doi

10.7150/ijbs.39098

subject

Has Abstract

pub_date

2020-02-17 00:00:00

pages

1288-1302

issue

8

issn

1449-2288

pii

ijbsv16p1288

journal_volume

16

pub_type

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