The MyD88 inhibitor TJ-M2010-2 suppresses proliferation, migration and invasion of breast cancer cells by regulating MyD88/GSK-3β and MyD88/NF-κB signalling pathways

Jian-Hua Liu; Chuang Chen; Ze-Yang Li; Zhi-Miao Zou; Dong-Cheng Gao; Xue Zhang; Xin-Wen Kuang; Zhi-Hong Sun; Wei-Jie Zheng; Ping Zhou; Sheng-Rong Sun

doi:10.1016/j.yexcr.2020.112157

The MyD88 inhibitor TJ-M2010-2 suppresses proliferation, migration and invasion of breast cancer cells by regulating MyD88/GSK-3β and MyD88/NF-κB signalling pathways

Exp Cell Res. 2020 Sep 15;394(2):112157. doi: 10.1016/j.yexcr.2020.112157. Epub 2020 Jun 29.

Authors

Affiliations

¹ Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, PR China.
² Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
³ Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: pzhou@tjh.tjmu.edu.cn.
⁴ Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, PR China. Electronic address: sun137@sina.com.

PMID: 32610185
DOI: 10.1016/j.yexcr.2020.112157

Abstract

MyD88 has been implicated in the tumourigenesis, metastasis and recurrence of breast cancer (BC). Here we utilized TJ-M2010-2 (TJ), an inhibitor of MyD88 homodimerimerization, and siMyD88 to suppress the function of MyD88 in MCF-7 and MDA-MB-231 cells. BC cells were treated in vitro and xenografted into nude mice to generate a model in vivo. TJ inhibited BC cell growth by impeding proliferation rather than by promoting apoptosis in vitro. Additionally, TJ and siMyD88 significantly attenuated cell migration and invasion, inhibited EMT-like progression and reduced cytokine (IL-6, IL-8, TGF-β1 and TNF-α) secretion induced by LPS. In vivo, TJ significantly hindered tumour growth in mice. Notably, TJ also decreased the secretion of IL-6, IL-8, TGF-β1, and TNF-α and M2 macrophage infiltration in the tumour microenvironment. The expression of MyD88, TRAF6, NF-κB p65, Snail, MMP-2, MMP-9, p-GSK-3β and p-Akt was significantly downregulated by TJ in BC cells and tumour tissues. Collectively, these results suggest that a MyD88 inhibitor (TJ) may be a promising therapeutic modality for treating BC patients.

Keywords: Breast cancer; Epithelial-mesenchymal transition; Metastasis; Myeloid differentiation factor 88; Tumour microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Breast Neoplasms / blood supply
Breast Neoplasms / pathology*
Cell Line, Tumor
Cell Movement / drug effects*
Cell Proliferation / drug effects
Cytokines / metabolism
Down-Regulation / drug effects
Epithelial-Mesenchymal Transition / drug effects
Female
Glycogen Synthase Kinase 3 beta / metabolism*
Humans
Lipopolysaccharides / pharmacology
Macrophages / drug effects
Macrophages / metabolism
Mice, Inbred BALB C
Mice, Nude
Myeloid Differentiation Factor 88 / antagonists & inhibitors*
Myeloid Differentiation Factor 88 / metabolism
NF-kappa B / metabolism*
Neoplasm Invasiveness
Neoplasm Proteins / metabolism
Neovascularization, Pathologic / pathology
Piperazines
Signal Transduction* / drug effects
Thiazoles / pharmacology*
Tumor Microenvironment / drug effects
Xenograft Model Antitumor Assays

Substances

5-(3-(4-(4-benzylpiperazin-1-yl)-N-(4-phenylthiazol-2-yl))propanamide
Cytokines
Lipopolysaccharides
Myeloid Differentiation Factor 88
NF-kappa B
Neoplasm Proteins
Piperazines
Thiazoles
Glycogen Synthase Kinase 3 beta