Erk2 but not Erk1 regulates crosstalk between Met and EGFR in squamous cell carcinoma cell lines

Gusenbauer, Simone; Zanucco, Emanuele; Knyazev, Pjotr; Ullrich, Axel

doi:10.1186/s12943-015-0319-z

Cited by 14 publications

(10 citation statements)

References 44 publications

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“…Therefore, the discovery of biomarkers that might predict the success of such targeted therapies would be advantageous. Functional cross talk between c-MET and other signaling receptors such as EGFR, transforming growth factor-β, Wnt, ERBB2, and insulin-like growth factor 1 receptor has been reported in several systems; moreover, this cross talk has emerged as a major mechanism of cancer progression and resistance to therapy [22] , [23] , [24] , [25] . Expectedly, CXCR4 receptor activation has been correlated with HGF/c-MET pathway activation in both rhabdomyosarcoma and breast cancer cells [15] , [26] .…”

Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial-Mesenchymal Transition in Gastric Cancer Cells

Song

et al. 2018

Translational Oncology

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The C-X-C motif chemokine receptor 4 (CXCR4) pathway can promote tumor metastasis but is dependent on cross talk with other signaling pathways. The MET proto-oncogene (c-MET) participates in metastasis and is highly expressed in gastric cancer. However, the relationship between CXCR4 and c-MET signaling and their mechanisms of action in gastric cancer metastasis remain unclear. In this study, in vitro experiments demonstrated that C-X-C motif chemokine ligand 12 (CXCL12)/CXCR4 induces epithelial-mesenchymal transition (EMT) and promotes migration in gastric cancer cells, which is accompanied by c-MET activation. These phenomena were reversed by c-MET inhibition. Further investigation revealed that c-MET activation correlated with its interaction with caveolin 1 in lipid rafts, induced by CXCL12. In clinical samples, we observed a significant positive association between CXCR4 expression and c-MET phosphorylation (r = 0.259, P = .005). Moreover, samples expressing both receptors were found to indicate significantly poorer patient prognosis (P < .001). These results suggest that CXCL12 induces EMT at least partially through cross talk between CXCR4 and c-MET signaling. In addition, changes in these pathways could have clinical importance for the treatment of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial-Mesenchymal Transition in Gastric Cancer Cells

Song

et al. 2018

Translational Oncology

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“…However, because of frequently reported cases of resistance to inhibitor treatment, it is essential to note the complexity of signal transduction that originates on the cell surface with stimulation of RTKs and continues through often shared downstream pathways. On the one hand, authors point out the importance of receptors’ crosstalk [ 52 , 53 ] and coactivation [ 7 , 54 ], gene copy amplification [ 55 ], and mutations [ 56 , 57 ], but on the other hand, they acknowledge the impact of simultaneously activated effector proteins involved in these pathways [ 21 ]. In our study, we decided to focus on selected elements of the Ras/MAPK and PI3K/Akt pathways, namely Erk and Akt, which are the main mediators of the pro-survival/anti-apoptotic signal.…”

Section: Discussionmentioning

confidence: 99%

Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines

Dratkiewicz

Pietraszek-Gremplewicz

Simiczyjew

et al. 2018

Oncotarget

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Melanoma is an aggressive cancer type with a high mortality rate and an elevated resistance to conventional treatment. Recently, promising new tools for anti-melanoma targeted therapy have emerged including inhibitors directed against frequently overexpressed receptors of growth factors implicated in the progression of this cancer. The ineffectiveness of single-targeted therapy prompted us to study the efficacy of treatment with a combination of foretinib, a MET (hepatocyte growth factor receptor) inhibitor, and gefitinib or lapatinib, EGFR (epidermal growth factor receptor) inhibitors. We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines. This combination of inhibitors significantly decreased Akt and Erk phosphorylation, while the drugs used independently were insufficient. Additionally, after treatment with pairs of inhibitors, cells became larger, with more pronounced stress fibers and abnormally shaped nuclei. We also noticed the appearance of polyploid cells and massive enrichment in the G2/M phase. Therefore, combination treatment was much more effective against melanoma cells than a single-targeted approach. Based on our results, we conclude that both EGFR and MET receptors might be effective targets in melanoma therapy. However, variation in their levels in patients should be taken into consideration.

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“…In addition, ERK1(p44) and ERK2(p42) have been reported to exert different effect on regulating cell metabolism. As an example, ERK2 but not ERK1 regulates the crosstalk between Met and EGFR in squamous cell carcinoma cell lines [ 21 ]. Active ERK2 is sufficient to mediate growth arrest and differentiation signaling [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Liu

Cai

Zheng

et al. 2015

IJMS

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The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCγ1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCγ1, mTOR and ERK in matrix degradation of OA will facilitate future attempts to manipulate ERK in OA prevention and therapy. Here, cultured human normal chondrocytes and OA chondrocytes were treated with different inhibitors or transfected with expression vectors, respectively. The levels of ERK, p-ERK, PLCγ1, p-PLCγ1, mTOR, p-mTOR and MMP-13 were then evaluated by Western blotting analysis. The results manifested that the expression level of ERK in human OA chondrocytes was lower than that in human normal articular chondrocytes, and the up-regulation of ERK could promote matrix synthesis, including the decrease in MMP-13 level and the increase in Aggrecan level in human OA chondrocytes. Furthermore, the PLCγ1/ERK axis and a mutual inhibition of mTOR and ERK were observed in human OA chondrocytes. Interestingly, activated ERK had no inhibitory effect on MMP-13 expression in PLCγ1-transformed OA chondrocytes. Combined with our previous study, the non-effective state of ERK activation by PLCγ1 on MMP-13 may be partly attributed to the inhibition of the PLCγ1/mTOR axis on the PLCγ1/ERK axis. Therefore, the study indicates that the mutual inhibition of ERK and mTOR is involved in PLCγ1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis as well as for its prevention and therapy.

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Erk2 but not Erk1 regulates crosstalk between Met and EGFR in squamous cell carcinoma cell lines

Cited by 14 publications

References 44 publications

The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial-Mesenchymal Transition in Gastric Cancer Cells

The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial-Mesenchymal Transition in Gastric Cancer Cells

Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

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