Anticancer Activities of Proteasome Inhibitor MG132 on Human Malignant Pleural Mesothelioma Cells

Details

• Personal Author:
  Chapman JA ; Lowry D ; Reynolds SH ; Yuan BZ
• Description:
  Malignant pleural mesothelioma (MPM), caused mainly by occupational or environmental exposure to asbestos, is an aggressive malignancy with a very poor prognosis. The general resistance of MPM to current therapeutic modalities and an ongoing increase in the incidence of MPM demonstrate the need for new treatments for this deadly disease. Proteasome inhibitors have emerged as a category of promising reagents for treating human cancers. MG132, the most commonly used proteasome inhibitor, has demonstrated its ability to induce apoptosis in some types of human cancer. In our initial attempt to determine the therapeutic effect of the proteasome inhibitors on human MPM, we chose MG132 as a prototype of the proteasome inhibitors and characterized its anti-cancer effects on NCI-H2502 and NCI-H2452, two human thoracic MPM cell lines. It was observed that as low as 0.5microM MG132 caused significant cell death in both MPM cell lines. Cell death derived mainly from apoptosis as evidenced by the appearance of a pre-G1 peak in flow cytometry analysis and propidium iodide staining. It was also observed that MG132-induced apoptosis in both MPM cell lines was accompanied by cleavage of the PARP and caspase 3 and 7 proteins. Treatment with either casapse 3 inhibitor or Z-VAD, a broad spectrum caspase inhibitor, resulted in inhibition of MG132-induced apoptosis, suggesting that MG132-induced apoptosis operates through a caspase-dependent mechanism. Further demonstration of caspase 9 activation, which is likely the consequence of MG132-induced Bid protein activation and the subsequent release of the Smac/Diablo protein from the mitochondria, suggests that a mitochondria-caspase 3 apoptosis pathway is responsible for mediating MG132-induced apoptosis in MPM cells. Analysis of MG132's effect on invasion by MPM cells, as tested by an in vitro Matrigel invasion assay, demonstrated that 0.1microM MG132, which showed no effect on apoptosis induction, significantly inhibited invasion by both NCI-H2452 and NCI-H2502 cells. MG132-inhibited tumor cell invasion was found to be associated with reduced Rac1 activity. These observations demonstrate proapoptotic and anti-invasion activities of MG132 on human MPM cells and lead to the suggestion that MG132 may be a useful reagent for clinical treatment of human 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 Lung-cancer Pulmonary-system-disorders Respiratory-system-disorders Therapeutic-agents
• ISSN:
  0197-016X
• Publisher:
  American Association for Cancer Research
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; Pennsylvania ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  48
• NIOSHTIC Number:
  nn:20032944
• Citation:
  Proceedings of the 98th American Association for Cancer Research Annual Meeting, April 14-18, 2007, Los Angeles, California. Philadelphia, PA: American Association for Cancer Research, 2007 Apr; 48:346
• CAS Registry Number:
  Asbestos (CAS RN 1332-21-4)
• Federal Fiscal Year:
  2007
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  Proceedings of the 98th American Association for Cancer Research Annual Meeting, April 14-18, 2007, Los Angeles, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:09691213134ddf79d28f682ffd96cbed8ae7bb2a55ebf2667543d63e0caaba8498987aad7e4bd4d73d4baa726aae794b67ea54e26625240f6812511a178d666e
• Download URL:
  https://stacks.cdc.gov/view/cdc/188700/cdc_188700_DS1.pdf
• File Type:
  [PDF - 475.77 KB ]