Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

Jiang, Weiwei; Cai, Fangfang; Xu, Huangru; Lu, Yao; Chen, Jia; Liu, Jia; Cao, Nini; Zhang, Xiangyu; Chen, Xiao; Huang, Qilai; Zhuang, Hongqin; Hua, Zhengli

doi:10.1007/s13238-020-00701-1

Cited by 32 publications

(31 citation statements)

References 54 publications

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“…Metacore GeneGo enrichment analysis identified that ERK5 positively regulated the proteins essential for actin cytoskeleton regulation, gelsolin, N-WASP, p-PLK1, and SPA1, and promoted a phenotypic switch from epithelial to mesenchymal in lung cancer cells [ 66 ]. MEK5 and ERK5 activation was also identified to upregulate TGF-β-mediated induction of EMT in a feedforward loop in lung cancer cells [ 66 ]. ERK5 activated focal adhesion kinase (FAK) at S910 position and upregulated upstream stimulatory factor (USF)1-mediated migration and invasion in metastatic lung cancer cells [ 66 ].…”

Section: Erk5 In Regulating the Metastatic Cascade And Therapeuticmentioning

confidence: 99%

“…MEK5 and ERK5 activation was also identified to upregulate TGF-β-mediated induction of EMT in a feedforward loop in lung cancer cells [ 66 ]. ERK5 activated focal adhesion kinase (FAK) at S910 position and upregulated upstream stimulatory factor (USF)1-mediated migration and invasion in metastatic lung cancer cells [ 66 ]. Transfection with dominant negative MEK5 and ERK5 isoforms simultaneously led to a significant reduction in lymph node and lung metastases of melanoma xenografts [ 66 ].…”

Section: Erk5 In Regulating the Metastatic Cascade And Therapeuticmentioning

confidence: 99%

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Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

et al. 2021

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Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

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Section: Erk5 In Regulating the Metastatic Cascade And Therapeuticmentioning

confidence: 99%

Section: Erk5 In Regulating the Metastatic Cascade And Therapeuticmentioning

confidence: 99%

Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

et al. 2021

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“…The top three TF were upstream stimulating factor1 (USF1), CCCTC binding factor (CTCF) and transcription factor YY1. USF1 related studies have shown that USF1 can transcriptionally up-regulate the expression of FAK in lung cancer, thus activating the FAK signal pathway and promoting cell migration (23). USF1 is involved in the transcription of many proteins and plays an important role as a regulator in many diseases, including tumors (24).Studies have shown that CTCF expression is involved in tumorigenesis( 25) and can be used as a transcription factor, to control gene expression by binding to the transcriptional initiation site(TSSs) of many genes (26).Some studies have shown that the binding and overexpression of transcription factor YY1 with BRCA1 promoter inhibits the proliferation and focus formation of nude mice cells and inhibits the growth of MDA-MB-231 tumor.…”

Section: Analysis Of Co-expression Genes Of Eif4e In Breast Cancermentioning

confidence: 99%

High Expression of eIF4E Regulates Immune Cell Infiltration and Leads to Poor Prognosis in Breast Cancer

Sun

et al. 2021

Preprint

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Background: The expression and activation of Eukaryotic translation initiation factor 4E (eIF4E) is related to tumor transformation and genesis, but the functional role and the mechanism whereby it drives immune infiltration in breast cancer remain uncertain.Methods: Multiple databases were used for assessing the expression and clinic-pathological features of eIF4E, after which ImmuCellAI and TIMER database were used to explore the relationship between eIF4E and immune infiltration of breast cancer. Finally, the genes co-expressed with eIF4E were identified by LinkedOmics. These genes were analyzed protein interaction network and TF-miRNA interaction network by Networkanalyst, and enriched by GO and KEGG. The key genes of immune markers were functionally annotated.Results: High expression of eIF4E was associated with poor overall survival (OS) and relapse-free survival (RFS) in breast cancer samples from multiple databases. It is notable that the expression of eIF4E is positively correlated with the infiltration of CD8+T cells, macrophages, neutrophils and dendritic cells. The expression of eIF4E is closely related to many immune markers in breast cancer. Functional analysis of co-expressed genes showed that they were involved in the biological process of human immune response. GO analysis showed that co-expressed immune marker genes were involved in human immune response, adaptive immune response, macrophage activation, extracellular structure organization and regulation of DNA metabolism process. KEGG enrichment showed that it was involved in inflammatory bowel disease, cell adhesion molecule pathway, JAK-STAT signal pathway, T cell receptor signal pathway and so on.Conclusions: These results suggest that high expression of eIF4E regulates immune cell infiltration, especially promotes macrophage M2 polarization by JAK / STAT6 and PI3K / AKT pathway, which is associated with poor prognosis of breast cancer patients. It is a valuable prognostic biomarker for breast cancer patients, and may be a potential therapeutic target in the future.

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“…The encoding sequence of mouse FAK was ampli ed from cDNA of B16F10 cells and cloned into pRK5-Flag vector. The promoter sequence of human and mouse FAK was ampli ed and cloned into pGL3 reporter vector just as the previous article (13). Actinomycin D (Act D) was purchased from Sigma.…”

Section: Plasmids Cell Lines and Reagentsmentioning

confidence: 99%

“…The LC-MS/MS analysis was performed as previously described (13). Brie y, after collecting the cells and obtaining the lysate, the peptide was puri ed using a Strata-XC18 column, and then the obtained peptide was labeled with the iTRAQ Reagent-8 plex Multiplex Kit (AB Sciex U.K. Limited) according to the manufacturer's instructions.…”

Section: Lc-ms/ms Analysis and Bioinformatics Analysismentioning

confidence: 99%

ADT-OH exhibits anti-metastatic activity on malignant melanoma through inhibition of FAK/Paxillin signaling pathways

Cai

et al. 2020

Preprint

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Background: Melanoma is a highly aggressive cancer, and its high metastasis results in a high lethality. Hydrogen sulfide (H2S) is now widely recognized as the third endogenous gas delivery substance and may play a key role in cancer biological processes. The present study was designed to evaluate the anti-metastatic effect of H2S-donor ADT-OH on melanoma cells and the underlying mechanism.Methods: Firstly, the effect of ADT-OH on the migration of melanoma cells was explored in vivo by the mouse footpad injection model and the mouse tail vein metastasis model. Tumor xenograft growth and tumor tissue H&E analyses were also measured in vivo. Then, the migration inhibitory effect and the underlying mechanism of ADT-OH on B16F10, B16F1 and A375 melanoma cell lines were evaluated by wound healing, transwell, western blot and immunofluorescence analyses. Results: Our data showed that ADT-OH inhibited the migration and invasion of melanoma cells significantly in vivo in three different animal models. Further research showed that ADT-OH significantly suppressed the migratory, invasive and adhesive properties of A375 and B16F10 cells as measured by the wound-healing and transwell assays. Mechanistically, ADT-OH treatment suppressed the EMT processes and reduced the enzymatic activity of FAK and Paxillin. Moreover, abnormal CSE/CBS and AKT signaling pathways in A375 and B16F10 cells were notably observed following ADT-OH treatment. Additionally, ADT-OH at higher concentration significantly inhibited the proliferation of highly metastatic melanoma A375 and B16F10 cells.Conclusions: Our results suggest that ADT-OH exerts anti-metastasis activity in melanoma cells by suppressing the EMT process through the CSE/CBS and FAK signaling pathways, and it might be used as an agent against metastatic melanoma in future.

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Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

Cited by 32 publications

References 54 publications

Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

High Expression of eIF4E Regulates Immune Cell Infiltration and Leads to Poor Prognosis in Breast Cancer

ADT-OH exhibits anti-metastatic activity on malignant melanoma through inhibition of FAK/Paxillin signaling pathways

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