A ROS/Akt/NF-κB Signaling Cascade Mediates Epidermal Growth Factor-Induced Epithelial-Mesenchymal Transition and Invasion in Human Breast Cancer Cells.

Content Provider	Europe PMC
Author	Min, Wei Li Wang, Bao Feng Liang, Bao Bao Zhang, Lun Pan, Ji Yuan Huang, Yi Zhao, Yang Lin, Shuai Zhao, Yi Han Zhang, Shu Qun Ma, Qing Yong
Copyright Year	2022
Abstract	BackgroundAs one of the most widely used anti-diabetic drugs for type II diabetes, metformin has been shown to exhibit anti-cancer activity in recent years. Epidermal growth factor (EGF) and its receptor, EGFR, play important roles in cancer metastasis in various tumors, including breast cancer. Epithelial-mesenchymal transition (EMT) is a critical process for cancer invasion and metastasis. In this study, we use EGF as a metastatic inducer to investigate the effect of metformin on cancer cell migration, invasion and EMT.MethodsHuman breast cancer MCF-7 cells were exposed to EGF with or without metformin or N-acetyl cysteine (NAC). The effects of metformin on breast cancer cell proliferation were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The production of reactive oxygen species (ROS) was tested using 2,7-dichlorodihydrofluorecein diacetate (DCFH-DA). The migratory and invasive abilities of tumor cells were analyzed using wound healing assay and transwell invasion assay, respectively. The expressions of E-cadherin, N-cadherin and Snail were tested using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting at mRNA and protein levels. The activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) were measured by western blotting.ResultsOur results showed that metformin inhibited breast cancer cell proliferation in a dose-dependent manner with or without EGF. EGF-induced alterations in cell morphology that are characteristic of EMT were reversed by metformin. Metformin also inhibited the EGF-modulated expression of E-cadherin, N-cadherin and Snail and further suppressed cell invasion and migration. In addition, metformin suppressed EGF-induced phosphorylation of Akt and NF-κB. ROS is involved in EGF-induced cancer invasion and activation of phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB pathway.ConclusionTaken together, these data indicate that metformin suppresses EGF-induced breast cancer cell migration, invasion and EMT through the inhibition of the PI3K/Akt/NF-κB pathway. These results provide a novel mechanism to explain the role of metformin as a potent anti-metastatic agent in breast cancer cells.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC9635793&blobtype=pdf
ISSN	19204531
Journal	World Journal of Oncology [World J Oncol]
Volume Number	13
DOI	10.14740/wjon1518
PubMed Central reference number	PMC9635793
Issue Number	5
PubMed reference number	36406192
e-ISSN	1920454X
Language	English
Publisher	Elmer Press
Publisher Date	2022-10-22
Access Restriction	Open
Rights License	This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2022, Min et al.
Subject Keyword	Metformin EGF EMT PI3K/Akt Breast cancer
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology