Document Detail


An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury.
MedLine Citation:
PMID:  21454801     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We hypothesized that normal human mesothelial cells acquire resistance to asbestos-induced toxicity via induction of one or more epidermal growth factor receptor (EGFR)-linked survival pathways (phosphoinositol-3-kinase/AKT/mammalian target of rapamycin and extracellular signal-regulated kinase [ERK] 1/2) during simian virus 40 (SV40) transformation and carcinogenesis. Both isolated HKNM-2 mesothelial cells and a telomerase-immortalized mesothelial line (LP9/TERT-1) were more sensitive to crocidolite asbestos toxicity than an SV40 Tag-immortalized mesothelial line (MET5A) and malignant mesothelioma cell lines (HMESO and PPM Mill). Whereas increases in phosphorylation of AKT (pAKT) were observed in MET5A cells in response to asbestos, LP9/TERT-1 cells exhibited dose-related decreases in pAKT levels. Pretreatment with an EGFR phosphorylation or mitogen-activated protein kinase kinase 1/2 inhibitor abrogated asbestos-induced phosphorylated ERK (pERK) 1/2 levels in both LP9/TERT-1 and MET5A cells as well as increases in pAKT levels in MET5A cells. Transient transfection of small interfering RNAs targeting ERK1, ERK2, or AKT revealed that ERK1/2 pathways were involved in cell death by asbestos in both cell lines. Asbestos-resistant HMESO or PPM Mill cells with high endogenous levels of ERKs or AKT did not show dose-responsive increases in pERK1/ERK1, pERK2/ERK2, or pAKT/AKT levels by asbestos. However, small hairpin ERK2 stable cell lines created from both malignant mesothelioma lines were more sensitive to asbestos toxicity than shERK1 and shControl lines, and exhibited unique, tumor-specific changes in endogenous cell death-related gene expression. Our results suggest that EGFR phosphorylation is causally linked to pERK and pAKT activation by asbestos in normal and SV40 Tag-immortalized human mesothelial cells. They also indicate that ERK2 plays a role in modulating asbestos toxicity by regulating genes critical to cell injury and survival that are differentially expressed in human mesotheliomas.
Authors:
Arti Shukla; Trisha F Barrett; Maximilian B MacPherson; Jedd M Hillegass; Naomi K Fukagawa; William A Swain; Kenneth J O'Byrne; Joseph R Testa; Harvey I Pass; Stephen P Faux; Brooke T Mossman
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-03-31
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  45     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-02     Completed Date:  2011-12-22     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  906-14     Citation Subset:  IM    
Affiliation:
Department of Pathology, University of Vermont College of Medicine, Burlington, 05405, USA.
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MeSH Terms
Descriptor/Qualifier:
Asbestos, Crocidolite / toxicity*
Cell Line
Cell Survival / drug effects
Enzyme Inhibitors / pharmacology
Gene Expression / drug effects
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Kinase 2 / antagonists & inhibitors
Mesothelioma / chemically induced*,  enzymology*
Mitogen-Activated Protein Kinase 1 / metabolism*
Pleural Neoplasms / chemically induced*,  enzymology*
RNA, Small Interfering / metabolism
Receptor, Epidermal Growth Factor / metabolism
Signal Transduction / drug effects
Grant Support
ID/Acronym/Agency:
CA-06927/CA/NCI NIH HHS; P01 CA114047/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/RNA, Small Interfering; 12001-28-4/Asbestos, Crocidolite; EC 2.7.1.-/MAP2K1 protein, human; EC 2.7.1.-/MAP2K2 protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.24/MAPK1 protein, human; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.12.2/MAP Kinase Kinase 1; EC 2.7.12.2/MAP Kinase Kinase 2
Comments/Corrections

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