Suppression of the Epidermal Growth Factor Receptor Inhibits Epithelial–Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells

Zhigang, Chang; Wei, Junmin; Qin, Cheng‐Feng; Hao, Kun; Xiang, Tian; Xie, Kun; Xie, Xing; Yang, Yue

doi:10.1007/s10620-012-2036-4

Cited by 27 publications

(23 citation statements)

References 34 publications

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“…The development of more effective and potent agents for the treatment of cancer is of particular importance considering the widespread problem of resistance to many anti-cancer agents used currently in the clinics, including EGFR inhibitors (28,29,43). In fact, although EGFR inhibitors have shown promise for the treatment of some tumors, their effects are inconsistent and largely affected by the many different mutations and alterations of EGFR encountered in cancer patients (46).…”

Section: Discussionmentioning

confidence: 99%

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

Kovačević

Menezes

Sahni

et al. 2016

Journal of Biological Chemistry

113

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N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-␤ pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

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Section: Discussionmentioning

confidence: 99%

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

Kovačević

Menezes

Sahni

et al. 2016

Journal of Biological Chemistry

113

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“…A recent report demonstrated that EGFR RNAi significantly improved cyclopamine sensitivity and decreased AKT and ERK phosphorylation in PC cells [37]. It also decreased migration and invasion capacity of cells, and also decreased the expression of mesenchymal markers such as vimentin and fibronectin, and increased the expression of epithelial marker E-cadherin, suggesting the reversal of EMT by suppression of EGFR expression in PANC-1 cells [38]. To further confirm the inter-relationship between EGFR and miR-146a , we used EGFR siRNA to knock-down EGFR expression and studied the consequence on EGFR expression and cellular behavior.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of miR-146a expression in a mouse model of pancreatic cancer affecting EGFR signaling

et al. 2014

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Aberrant expression of microRNAs (miRNAs) plays important roles in the development and progression of pancreatic cancer (PC). Expression analysis of miR-146a in human PC tissues showed decreased expression in about 80% of samples compared to corresponding noncancerous tissue. Moreover, expression of miR-146a in eight PC cell lines, and in pancreatic tissues obtained from transgenic mouse models of K-Ras (K), Pdx1-Cre (C), K-Ras;Pdx1-Cre (KC) and K-Ras;Pdx1-Cre;INK4a/Arf (KCI), showed down-regulation of miR-146a expression in KCI mice which was in part led to over-expression of its target gene, epidermal growth factor receptor (EGFR). Treatment of PC cells with CDF, a novel synthetic compound, led to reexpression of miR-146a, resulting in the down-regulation of EGFR expression. Moreover, reexpression of miR-146a by stable transfection or treatment with CDF in vivo (xenograft animal model) resulted in decreased tumor growth which was consistent with reduced EGFR, ERK1, ERK2, and K-Ras expression. Further knock-down of miR-146a in AsPC-1 cells led to the upregulation of EGFR expression and showed increased clonogenic growth. In addition, knockdown of EGFR by EGFR siRNA transfection of parental AsPC-1 cells and AsPC-1 cells stably transfected with pre-miR-146a resulted in decreased invasive capacity, which was further confirmed by reduced luciferase activity in cells transfected with pMIR-Luc reporter vector containing miR-146a binding site. Collectively, these results suggest that the loss of expression of miR-146a is a fundamental mechanism for over-expression of EGFR signaling and that reexpression of miR-146a by CDF treatment could be useful in designing personalized strategy for the treatment of human PC.

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“…EGFR signaling has also been linked to EMT [172]. Therapeutic targeting EGFR and its inhibition can cause a reversal of EMT in human pancreatic cancer [172].…”

Section: Role Of Neu1 Sialidase In Cancer Cell Survival and Acquired mentioning

confidence: 99%

“…EGFR signaling has also been linked to EMT [172]. Therapeutic targeting EGFR and its inhibition can cause a reversal of EMT in human pancreatic cancer [172]. Other studies have suggested the potential role of growth factor receptor signaling in establishing chemoresistance of cancer cells [173–176].…”

Section: Role Of Neu1 Sialidase In Cancer Cell Survival and Acquired mentioning

confidence: 99%

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

2016

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Several of the growth factors and their receptor tyrosine kinases (RTK) such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin are promising candidate targets for cancer therapy. Indeed, tyrosine kinase inhibitors (TKI) have been developed to target these growth factors and their receptors, and have demonstrated dramatic initial responses in cancer therapy. Yet, most patients ultimately develop TKI drug resistance and relapse. It is essential in the clinical setting that the targeted therapies are to circumvent multistage tumorigenesis, including genetic mutations at the different growth factor receptors, tumor neovascularization, chemoresistance of tumors, immune-mediated tumorigenesis and the development of tissue invasion and metastasis. Here, we identify a novel receptor signaling platform linked to EGF, NGF, insulin and TOLL-like receptor (TLR) activations, all of which are known to play major roles in tumorigenesis. The importance of these findings signify an innovative and promising entirely new targeted therapy for cancer. The role of mammalian neuraminidase-1 (Neu1) in complex with matrix metalloproteinase-9 and G protein-coupled receptor tethered to RTKs and TLRs is identified as a major target in multistage tumorigenesis. Evidence exposing the link connecting growth factor-binding and immune-mediated tumorigenesis to this novel receptor-signaling paradigm will be reviewed in its current relationship to cancer.

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Suppression of the Epidermal Growth Factor Receptor Inhibits Epithelial–Mesenchymal Transition in Human Pancreatic Cancer PANC-1 Cells

Abstract: Suppression of EGFR expression can significantly inhibit EMT of pancreatic cancer PANC-1 cells. The mechanism may be related with the down-regulation of the expression of transcription factors snail and slug.

Cited by 27 publications

References 34 publications

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

Deregulation of miR-146a expression in a mouse model of pancreatic cancer affecting EGFR signaling

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

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