MCP-1-induced ERK/GSK-3β/Snail signaling facilitates the epithelial–mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells

Abstract

Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic cytokine that can bind to its receptor cysteine-cysteine chemokine receptor 2 (CCR2) and plays an important role in breast cancer cell metastasis. However, the molecular mechanisms underlying MCP-1-induced alterations in cellular functions during tumor progression are poorly understood. Here, we showed that MCP-1 stimulated the epithelial-mesenchymal transition (EMT) and induced the tumorigenesis of breast cancer cells by downregulating E-cadherin, upregulating vimentin and fibronectin, activating matrix metallopeptidase-2 (MMP-2), and promoting migration and invasion. Moreover, MCP-1 treatment reduced glycogen synthase kinase-3β (GSK-3β) activity via the MEK/ERK-mediated phosphorylation of serine-9 in MCF-7 cells. The inhibition of MEK/ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3β and decreased the expression of Snail, an EMT-related transcription factor, leading to the inhibition of MCF-7 cell migration and invasion. Inactivation of GSK-3β by LiCl (lithium chloride) treatment notably increased MMP-2 activity, vascular endothelial growth factor expression and EMT of MCF-7 cells. These findings revealed that MCP-1-induced EMT and migration are mediated by the ERK/GSK-3β/Snail pathway, and identified a potential novel target for therapeutic intervention in breast cancer. Cellular & Molecular Immunology

Knockdown of Radixin Suppresses Gastric Cancer Metastasis In Vitro by Up-Regulation of E-Cadherin via NF-κB/Snail Pathway

“…Furthermore, we addressed the underlying mechanism by which the expression of snail was down-regulated in the radixin knockdown cells. There are at least three signaling pathways contributing to the regulation of snail and E-cadherin, including ERK pathway, Akt pathway and NF-κB pathway: The inhibition of ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3β and decreased the expression of snail, leading to the restoration of E-cadherin in MCF-7 cells [30]; Activation of Akt led to a significant reduction in E-cadherin expression following nuclear accumulation of snail, suggesting a role for the Akt signaling pathway in the transient repression of E-cadherin in prostate cancer [31]; Treatment with Celastrus orbiculatus induced nuclear exclusion of NF-κB, which in turn led to down-regulation of snail in SGC-7901 cells. As a result, the expression of E-cadherin was up-regulated and metastatic potential was suppressed [32].…”

“…Currently, it is generally accepted that the suppression of E-cadherin expression mainly occurs at transcriptional level, and several transcription factors that repress its transcription have been recognized, including zinc finger factors snail, slug, zeb1 and zeb2, basic helixloop-helix factors E47 and twist [27][28][29]. Furthermore, increasing evidence revealed that these transcription factors could be regulated via several signaling cascades, including ERK pathway, Akt pathway and NF-κB pathway [30][31][32].…”

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Further, EMT confers on cancer cells mesenchymal traits and an ability to enter the CSC state. Recent studies show that breast tumor progression and EMT are activated by ERK/GSK-3β/Snail (Li et al, 2016) and both NF-κB and β-catenin signaling (Luo et al, 2016) mediated by MCP-1 and VEGF/NPR respectively. In this context, it may speculate that ERK/GSK-3β/Snail and NF-κB and β-catenin signaling may induce MSCs to secret tumor initiating growth factors that stimulates sphere formation or growth of CSC-like cell.…”

PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma

“…In our vitro experiments, we further elucidated that PRKAR1A deficiency up-regulated snail expression by the activation of ERK pathway, which was critical for the initiation and progression of numerous cancers414243. ERK kinase could activate Snail to further regulate EMT4445. Collectively, through the modulation of ERK/Snail/E-cadherin signaling pathway, PRKAR1A could act as a tumor suppressor gene by inhibiting lung adenocarcinoma growth and metastasis.…”