An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury

Shukla, Arti, Barrett, Trisha F., MacPherson, Maximilian B., Hillegass, Jedd M., Fukagawa, Naomi K., Swain, William A., O'Byrne, Kenneth J., Testa, Joseph R., Pass, Harvey I., Faux, Stephen P., & Mossman, Brooke T. (2011) An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury. American Journal of Respiratory Cell and Molecular Biology, 45(5), pp. 906-914.

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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 linkedto 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.

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6 citations in Web of Science®
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ID Code: 65691
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Asbestos, Epidermal growth factor receptor, Mesothelioma, Protein kinase B/AKT, Toxicity, 1, 4 diamino 1, 4 bis(2 aminophenylthio) 2, 3 dicyanobutadiene, 4 (3 chloroanilino) 6, 7 dimethoxyquinazoline, crocidolite, mammalian target of rapamycin, mitogen activated protein kinase 1, mitogen activated protein kinase 3, mitogen activated protein kinase inhibitor, phosphatidylinositol 3 kinase, protein kinase B, small interfering RNA, article, cancer cell culture, carcinogenesis, cell survival, cell transformation, cell viability, concentration response, cytotoxicity, human, human cell, malignant mesothelioma, mesothelioma cell, mesothelium cell, protein phosphorylation, Simian virus 40, transient transfection, tumor cell, Asbestos, Crocidolite, Cell Line, Enzyme Inhibitors, Gene Expression, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mitogen-Activated Protein Kinase 1, Pleural Neoplasms, Receptor, Epidermal Growth Factor, RNA, Small Interfering, Signal Transduction, Mammalia
DOI: 10.1165/rcmb.2010-0282OC
ISSN: 1044-1549
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2011 American Thoracic Society
Deposited On: 06 Jan 2014 06:15
Last Modified: 14 Mar 2014 05:16

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