PMID- 25446090
OWN - NLM
STAT- MEDLINE
DCOM- 20150210
LR  - 20181202
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 455
IP  - 3-4
DP  - 2014 Dec 12
TI  - Treatment with insulin-like growth factor 1 receptor inhibitor reverses 
      hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer.
PG  - 332-8
LID - S0006-291X(14)02017-8 [pii]
LID - 10.1016/j.bbrc.2014.11.014 [doi]
AB  - Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid 
      tumors including non-small cell lung cancer (NSCLC), and enhanced activation of 
      IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition 
      (EMT) has been established as one of the mechanisms responsible for cancer 
      progression and metastasis, and microenvironment conditions, such as hypoxia, 
      have been shown to induce EMT. The purposes of this study were to address the 
      role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether 
      inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines 
      A549 and HCC2935 were exposed to hypoxia to investigate the expression of 
      EMT-related genes and phenotypes. Gene expression analysis was performed by 
      quantitative real-time PCR and cell phenotypes were studied by morphology 
      assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells 
      exhibited a spindle-shaped morphology with increased cell motility reminiscent of 
      EMT, and demonstrated the loss of E-cadherin and increased expression of 
      fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF 
      binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor beta1 
      (TGFbeta1). Inhibition of hypoxia-inducible factor 1alpha (HIF1alpha) with YC-1 abrogated 
      activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. 
      Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored 
      E-cadherin expression, and reduced expression of fibronectin and vimentin. 
      Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated 
      that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that 
      IGF1R inhibition reversed these phenomena. These results suggest a potential role 
      for targeting IGF1R in the prevention of hypoxia-induced cancer progression and 
      metastasis mediated by EMT.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Nurwidya, Fariz
AU  - Nurwidya F
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Takahashi, Fumiyuki
AU  - Takahashi F
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan. Electronic address: 
      fumiyuki@dol.hi-ho.ne.jp.
FAU - Kobayashi, Isao
AU  - Kobayashi I
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Murakami, Akiko
AU  - Murakami A
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Kato, Motoyasu
AU  - Kato M
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Minakata, Kunihiko
AU  - Minakata K
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Nara, Takeshi
AU  - Nara T
AD  - Department of Molecular and Cellular Parasitology, Juntendo University Graduate 
      School of Medicine, Tokyo, Japan.
FAU - Hashimoto, Muneaki
AU  - Hashimoto M
AD  - Department of Molecular and Cellular Parasitology, Juntendo University Graduate 
      School of Medicine, Tokyo, Japan.
FAU - Yagishita, Shigehiro
AU  - Yagishita S
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Baskoro, Hario
AU  - Baskoro H
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Hidayat, Moulid
AU  - Hidayat M
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Shimada, Naoko
AU  - Shimada N
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
FAU - Takahashi, Kazuhisa
AU  - Takahashi K
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan; Research Institute for Diseases of Old Ages, Juntendo 
      University Graduate School of Medicine, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141115
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antigens, CD)
RN  - 0 (CDH1 protein, human)
RN  - 0 (Cadherins)
RN  - 0 (Fibronectins)
RN  - 0 (IGFBP3 protein, human)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 3)
RN  - 0 (Vimentin)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Antigens, CD
MH  - Cadherins/metabolism
MH  - Carcinoma, Non-Small-Cell Lung/*metabolism
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Disease Progression
MH  - *Epithelial-Mesenchymal Transition
MH  - Fibronectins/metabolism
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Insulin-Like Growth Factor Binding Protein 3/metabolism
MH  - Insulin-Like Growth Factor I/metabolism
MH  - Lung Neoplasms/*metabolism
MH  - Neoplasm Metastasis
MH  - Oxygen/metabolism
MH  - Phenotype
MH  - Receptor, IGF Type 1/*antagonists & inhibitors
MH  - Signal Transduction
MH  - Vimentin/metabolism
MH  - Wound Healing
OTO - NOTNLM
OT  - EMT
OT  - IGF1R signaling
OT  - NSCLC
EDAT- 2014/12/03 06:00
MHDA- 2015/02/11 06:00
CRDT- 2014/12/03 06:00
PHST- 2014/10/27 00:00 [received]
PHST- 2014/11/07 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
AID - S0006-291X(14)02017-8 [pii]
AID - 10.1016/j.bbrc.2014.11.014 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):332-8. doi: 
      10.1016/j.bbrc.2014.11.014. Epub 2014 Nov 15.