RRC ID |
43977
|
Author |
Shimojo Y, Akimoto M, Hisanaga T, Tanaka T, Tajima Y, Honma Y, Takenaga K.
|
Title |
Attenuation of reactive oxygen species by antioxidants suppresses hypoxia-induced epithelial-mesenchymal transition and metastasis of pancreatic cancer cells.
|
Journal |
Clin Exp Metastasis
|
Abstract |
Hypoxia has been shown to promote metastasis of cancer cells through induction of epithelial-mesenchymal transition (EMT). It is also known to cause generation of reactive oxygen species (ROS). We investigated here the role of ROS in hypoxia-induced EMT and whether attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastasis of human pancreatic cancer cells in a xenograft nude mouse model. PANC-1 and MiaPaCa-2 cells exposed to hypoxia (1 % O(2)) showed increased ROS generation and characteristic changes of EMT such as morphological changes, enhanced invasiveness, and upregulation of EMT regulators, SLUG, SNAI1 and TWIST. The antioxidants N-acetylcysteine (NAC) and ebselen significantly suppressed EMT and the expression of EMT regulators during hypoxia. NAC abrogated activation of HIF-1α and NF-κB, both of which were found to play an active role in hypoxia-induced EMT. Administration of NAC to nude mice with orthotopic tumors suppressed the expression of EMT regulators in hypoxic areas and significantly inhibited hepatic metastasis. Together, the present findings demonstrate that attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastatic phenotype, suggesting that antioxidants may be of therapeutic value in treating pancreatic cancers.
|
Volume |
30(2)
|
Pages |
143-54
|
Published |
2013-2-1
|
DOI |
10.1007/s10585-012-9519-8
|
PMID |
22833345
|
MeSH |
Acetylcysteine / therapeutic use*
Animals
Antioxidants / therapeutic use*
Apoptosis / drug effects
Blotting, Western
Cell Adhesion
Cell Movement
Cell Proliferation
Epithelial-Mesenchymal Transition / drug effects*
Female
Fluorescent Antibody Technique
Humans
Hypoxia / pathology*
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Liver Neoplasms / metabolism
Liver Neoplasms / prevention & control*
Liver Neoplasms / secondary
Mice
Mice, Nude
NF-kappa B / antagonists & inhibitors
NF-kappa B / genetics
NF-kappa B / metabolism
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / prevention & control*
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Reactive Oxygen Species / metabolism*
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Snail Family Transcription Factors
Transcription Factors / genetics
Transcription Factors / metabolism
Tumor Cells, Cultured
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism
|
IF |
3.027
|
Times Cited |
46
|
WOS Category
|
ONCOLOGY
|
Resource |
Human and Animal Cells |
PANC-1(RCB2095)
MIA Paca2(RCB2094) |