Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells

Details

• Personal Author:
  Chapman JA ; Reynolds SH ; Yuan BZ ; Chapman JA ; Reynolds SH ; Yuan BZ
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Cancer Cell-cultures Cell-function Cellular-function Cellular-reactions Chemotherapy Lung-cancer Mesothelial-cells Pulmonary-system-disorders Respiratory-system-disorders Therapeutic-agents

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• ISSN:
  1944-7124
• Document Type:
  Text
• Genre:
  Journal Article ; Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division ; HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Pages in Document:
  129-140
• Volume:
  1
• Issue:
  3
• NIOSHTIC Number:
  nn:20034619
• Citation:
  Transl Oncol 2008 Sep; 1(3):129-140
• Contact Point Address:
  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
• Email:
  bby1@cdc.gov
• CAS Registry Number:
  Asbestos (CAS RN 1332-21-4) ; Asbestos (CAS RN 1332-21-4)
• Federal Fiscal Year:
  2008
• NORA Priority Area:
  Manufacturing ; Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Translational Oncology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:09154797186cf83132c5daeb19c444b00ef7cd270e9b8ddff05b3bf785cafd9d49f6e105bfd8418d21e2348c4738580b105c2b41d36c35217af77185b3ddefea
• Download URL:
  https://stacks.cdc.gov/view/cdc/186762/cdc_186762_DS1.pdf
• File Type:
  [PDF - 1005.41 KB ]