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Proteasome inhibitor MG132 induces apoptosis and inhibits invasion of human malignant pleural mesothelioma cells.

Authors
Yuan-BZ; Chapman-JA; Reynolds-SH
Source
Transl Oncol 2008 Sep; 1(3):129-140
NIOSHTIC No.
20034619
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive malignancy tightly associated with asbestos exposure. The increasing incidence of MPM and its resistance to all therapeutic modalities necessitate an urgent development of new treatments for MPM. Proteasome inhibitors (PIs) have emerged as promising agents for treating human cancers that are refractory to current chemotherapies. In this study, we characterized MG132, a commonly used PI, for its proapoptotic and anti-invasion activities in NCI-H2452 and NCI-H2052 human thoracic MPM cell lines to determine the therapeutic effect of PIs on MPM. We found that as low as 0.5 uM MG132 caused a significant apoptosis in both cell lines as evidenced by DNA damage, cleavage of poly ADP-ribose polymerase and caspases 3, 7, and 9, and mitochondrial release of Smac/DIABLO and Cytochrome c. Mitochondrial caspase activation was found to be the underlying mechanism of the MG132-induced apoptosis. Mcl-1, among the Bcl-2 and IAP (inhibitor of apoptosis protein) antiapoptotic family proteins tested, was proved to be a major inhibitor of the MG132-induced apoptosis in MPM cells. Meanwhile, subapoptotic doses of MG132 inhibited the invasion of both MPM cell lines through reducing Rac1 activity. These observations demonstrate that MG132 possesses proapoptotic and anti-invasion activities in human MPM cells, therefore encouraging further investigations on the value of PIs for treating MPM.
Keywords
Cancer; Lung-cancer; Respiratory-system-disorders; Pulmonary-system-disorders; Cellular-reactions; Therapeutic-agents; Cell-cultures; Cell-function; Cellular-function; Mesothelial-cells; Chemotherapy
Contact
Bao-Zhu Yuan, Laboratory of Molecular Genetics, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, M/S: L-3014, Morgantown, WV 26505
CAS No.
1332-21-4
Publication Date
20080901
Document Type
Journal Article
Email Address
bby1@cdc.gov
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Issue of Publication
3
ISSN
1944-7124
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Translational Oncology
State
WV
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