Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line

Rho, Jin Kyung; Choi, Yun Jung; Lee, Jin Kyung; Ryoo, Baek‐Yeol; Na, Im Il; Yang, Sung Hyun; Kim, Cheol Hyeon; Lee, Jae Cheol

doi:10.1016/j.lungcan.2008.05.017

Cited by 194 publications

(195 citation statements)

References 47 publications

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“…Previous studies also revealed that EMT is crucial in drug resistance to EGFR inhibitor in NSCLC (27) and promotes the cell invasion and metastatic property. NSCLC cells expressing epithelial phenotype are more sensitive to EGFR inhibition than NSCLC lines expressing mesenchymal phenotype such as vimentin (28)(29)(30). Here, western blotting showed that E-cadherin and β-catenin as epithelial phenotypes were upregulated, while Slug as a mesenchymal phenotype was downregulated in ZNF746 siRNA vector-transfected H460 NSCLC cells compared to untreated control, indicating that the silencing of ZNF746 inhibits invasion-metastasis cascades via regulation of EMT molecules.…”

Section: Discussionmentioning

confidence: 76%

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

et al. 2013

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Abstract. Although ZNF746, also known as Parkin-interacting substrate (PARIS), has been reported to suppress peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and its target gene NRF-1 leading to the neurodegeneration in Parkinson's disease, its function in tumorigenesis has yet to be investigated. Thus, in the present study, the role of ZNF746 in the invasion and epithelial to mesenchymal transition (EMT) in H460 non-small cell lung cancer (NSCLC) cells was investigated. Invasion assay showed that inhibition of ZNF746 using siRNA transfection inhibited the invasion of H460 NSCLC cells using Boyden chamber. Quantitative PCR (qPCR) analysis revealed that the silencing of ZNF746 attenuated the expression of matrix metalloproteinase (MMP)1, MMP2 and MMP9, but not MMP7, in H460 NSCLC cells. Immunoblotting assay revealed that the expression of E-cadherin and β-catenin of epithelial phenotype was upregulated, while Slug was downregulated in ZNF746 siRNA-transfected H460 NSCLC cells. Accordingly, the mRNA expression of E-cadherin was upregulated while vimentin or Slug, Twist, ZEB as EMT key transcriptional factors were suppressed in ZNF746 siRNAtransfected H460 NSCLC cells. Also, mRNA expression of transcriptional marker Nanog and Octamer-binding transcription factor 4 (OCT4), known to enhance malignancy and metastasis in lung adenocarcinoma, was suppressed in ZNF746 siRNA-transfected H460 NSCLC cells. Notably, the endogenous expression of ZNF746 was induced in parallel with Twist at the protein level during hypoxia. Overall, our findings suggest that inhibition of ZNF746 suppresses the invasion and EMT molecules in H460 NSCLC cells and ZNF746 may be an important target molecule in lung tumorigenesis.

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Section: Discussionmentioning

confidence: 76%

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

et al. 2013

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“…Furthermore, morphologic changes were also observed in resistant cells, which were reminiscent of epithelialto-mesenchymal transition. However, because E-cadherin loss and delocalization were not observed, epithelial-to-mesenchymal transition is unlikely to have been responsible for gefitinib and erlotinib resistance, although we previously suggested that epithelial-to-mesenchymal transition might be a mechanism of gefitinib resistance (29). Further investigations on how MET activity increases during cell proliferation and on what morphologic changes are present in resistant cells are needed.…”

Section: Mol Cancer Res 2009;7(10) October 2009mentioning

confidence: 91%

The Role of MET Activation in Determining the Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Rho

Choi

Lee

et al. 2009

Molecular Cancer Research

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The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib-or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more resistance to gefitinib and erlotinib and acquired cross-resistance to other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this seemed to be the cause of drug resistance. Resistant cells also showed MET activation, although gene amplification was not detected. Furthermore, the induction of MET activity was not found to be associated with sensitivity to EGFR-TKIs. Interestingly, increased passage number without exposure to gefitinib or erlotinib caused MET activation, but this did not affect sensitivity to EGFR-TKIs. In addition, hepatocyte growth factor was found to block the ability of EGFR-TKIs to inhibit MET activation. However, sustained MET activation by hepatocyte growth factor did not modulate the cellular effects of gefitinib or erlotinib. Rather, activated MET enhanced migration and invasion abilities. Summarizing, MET activation may be acquired during cancer cell proliferation and enhances migratory and invasive abilities without affecting cellular sensitivity to EGFR-TKIs. Accordingly, the present study suggests that MET activation caused by factors other than MET gene amplification is not a suitable surrogate marker of resistance to EGFR-TKIs.

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“…Growing evidence indeed supports the assumption that EMT is as a transient state providing cells with a higher stress threshold and could thereby constitute an escape from apoptosis. In vitro, oxaliplatin-resistant colorectal cancer cells, tamoxifen-resistant breast cancer cells, gefintinib-resistant lung cancer cells as well as gemcitabineresistant pancreatic cells have been shown to have undergone an EMT (Hiscox et al, 2006;Yang et al, 2006;Rho et al, 2009). Additional characteristics of 'resistance' in cancer stem cells might also be provided through an EMT, such as lower levels of ROS and consequent protection of their genomes (Diehn et al, 2009).…”

Section: Oncogenic and Pro-metastatic Potentials Of Twist Proteinsmentioning

confidence: 99%

TWISTing an embryonic transcription factor into an oncoprotein

et al. 2010

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Over the past decade, the reactivation of TWIST embryonic transcription factors has been described as a frequent event and a marker of poor prognosis in an impressive array of human cancers. Growing evidence now supports the premise that these cancers hijack TWIST's embryonic functions, granting oncogenic and metastatic properties. In this review, we report on the history and recent breakthroughs in understanding TWIST protein functions and the emerging role of the associated epithelialmesenchymal transition (EMT) in tumorigenesis. We then broaden the discussion to address the general contribution of reactivating embryonic programs in cancerogenesis.

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Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line

Cited by 194 publications

References 47 publications

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

The Role of MET Activation in Determining the Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

TWISTing an embryonic transcription factor into an oncoprotein

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