Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial–mesenchymal transition in non-small cell lung cancer

Nurwidya, Fariz; Takahashi, Fumiyuki; Kobayashi, Isao; Murakami, Akiko; Kato, Motoyasu; Minakata, Kenji; Nara, Takeshi; Hashimoto, Muneaki; Yagishita, Shigehiro; Baskoro, Hario; Hidayat, Moulid; Shimada, Naoki; Takahashi, Kazuhisa

doi:10.1016/j.bbrc.2014.11.014

Cited by 38 publications

(38 citation statements)

References 20 publications

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“…IGF-I has been shown to stimulate vimentin rearrangement in a variety of cell types. (22) Although stimulating vimentin rearrangement could be related to its interaction with RPTPβ, our studies clearly show that serine phosphorylation of the vimentin head domain is required. Serine phosphorylation of the head domain has been shown to regulate differential changes in vimentin-protein interactions and changes in target protein function.…”

Section: Discussionmentioning

confidence: 66%

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

Shen

Rosen

et al. 2016

Journal of Bone and Mineral Research

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Insulin like growth factor I (IGF-I) and insulin like growth factor binding protein-2 (IGFBP-2) function coordinately to stimulate AKT and osteoblast differentiation. IGFBP-2 binding to receptor protein tyrosine phosphatase β (RPTPβ) stimulates polymerization and inactivation of phosphatase activity. Because phosphatase and tensin homolog (PTEN) is the primary target of RPTPβ, this leads to enhanced PTEN tyrosine phosphorylation and inactivation. However RPTPβ inactivation also requires IGF-I receptor activation. The current studies were undertaken to determine the mechanism by which IGF-I mediates changes in RPTPβ function in osteoblasts. IGFBP-2/IGF-I stimulated vimentin binding to RPTPβ and this was required for RPTPβ polymerization. Vimentin serine phosphorylation mediated its binding to RPTPβ and PKCζ was identified as the kinase that phosphorylated vimentin. To determine the mechanism underlying IGF-I stimulation of PKCζ-mediated vimentin phosphorylation, we focused on insulin receptor substrate–1 (IRS-1). IGF-I stimulated IRS-1 phosphorylation and recruitment of PKCζ and vimentin to phospho-IRS-1. IRS-1 immunoprecipitates containing PKCζ and vimentin were used to confirm that activated PKCζ directly phosphorylated vimentin. PKCζ does not contain a SH-2 domain that is required to bind to phospho-IRS-1. To determine the mechanism of PKCζ recruitment we analyzed the role of p62 (a PKCζ binding protein) that contains a SH2 domain. Exposure to differentiation medium plus IGF-I stimulated PKCζ/p62 association. Subsequent analysis showed the p62/PKCζ complex was co-recruited to IRS-1. Peptides that disrupted p62/PKCζ or p62/IRS-1 inhibited IGF-I/IGFBP-2 stimulated PKCζ activation, vimentin phosphorylation, PTEN tyrosine phosphorylation, AKT activation, and osteoblast differentiation. The importance of these signaling events for differentiation was confirmed in primary mouse calvarial osteoblasts. These results demonstrate the cooperative interaction between RPTPβ and the IGF-I receptor leading to a coordinated series of signaling events that are required for osteoblast differentiation. Our findings emphasize the important role IRS-1 plays in modulating these signaling events and confirm its essential role in facilitating osteoblast differentiation.

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Section: Discussionmentioning

confidence: 66%

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

Shen

Rosen

et al. 2016

Journal of Bone and Mineral Research

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“…From in vitro experiments, it is known that EMT can be initiated by stimulation with IGF1 and reversed when adding the IGF1R inhibitor AEW541 (64). IGF1R activation is also a proposed resistance mechanism to EGFR TKIs in NSCLC cell lines (53,65).…”

Section: Igf1rmentioning

confidence: 99%

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and resistance to lung cancer therapy Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The 5-year survival remains at 10-15% despite advances in treatment options.Erlotinib, a TKI targeting EGFR, was initially explored as a second-line treatment in NSCLC patients progressing on standard chemotherapy. Survival was prolonged compared to placebo (1). However, erlotinib was soon discovered to be especially efficient in patients with a mutation in the tyrosine kinase domain of EGFR. These patients are nowThe role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer Correspondence to: Anders Lade Nielsen. Department of Biomedicine, Bartholin Building, Aarhus University, DK-8000, Aarhus C, Denmark.Email: aln@biomed.au.dk.Abstract: Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFRdirected tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10-20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs.Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs.Keywords: Epidermal growth factor receptor (EGFR); epithelial to mesenchymal transition (EMT); non-small cell lung cancer (NSCLC); tyrosine kinase inhibitor (TKI)

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“…A meta-analysis suggested IGF1R positive expression as an unfavorable factor associated with smoking status and tumor size for disease free survival in NSCLC patients [32]. This receptor also connects with hypoxia closely for that hypoxia induces epithelial-mesenchymal transition in NSCLC cells through activation of IGF1R [33]. Furthermore, hypoxia increases the population of lung cancer stem cell resistant to gefitinib in EGFR mutation-positive NSCLC by activating IGF1R [34].…”

Section: Discussionmentioning

confidence: 99%

Plasma MiRNA alterations between NSCLC patients harboring Del19 and L858R EGFR mutations

et al. 2016

Oncotarget

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Based on recognition of driver mutations, treatment paradigm for non-small-cell lung cancer (NSCLC) patients has been shifted. However, recently exon 19 deletion mutation (del19) of epidermal growth factor receptor (EGFR) clearly shows better clinical benefit over single-point substitution mutation L858R in exon 21 (L858R). The aim of this study was to investigate the difference by analyzing the expression of plasma microRNAs (miRNAs) of NSCLC patients with EGFR mutation del19 or L858R. MiRNA microarray of plasma from patients' blood identified 79 mapped, network-eligible miRNAs (fold > 5), of which 76 were up regulated and 3 were down regulated. Genetic network was performed with Ingenuity Pathway Analysis (IPA). Among analysis, MYC, Argonaute2 (AGO2), Y-box binding protein 1 (YBX1), cyclin E1 (CCNE1) were involved in organismal abnormalities and cancer. Our findings provide information on the epigenetic signature of the two major sensitive mutations among NSCLC and add to the understanding of mechanisms underlying the different outcomes.

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Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial–mesenchymal transition in non-small cell lung cancer

Cited by 38 publications

References 20 publications

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Plasma MiRNA alterations between NSCLC patients harboring Del19 and L858R EGFR mutations

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