TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages

Details

• Personal Author:
  Chapman J ; Ding M ; Jiang B ; Reynolds SH ; Rojanasakul Y ; Wang J ; Yuan B-Z
• Description:
  Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. Methods: Proteasome inhibitors (PIs) and TNFá-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. Results: Treatment with 0.5-1 uM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10- 20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. Conclusion: The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs. [Description provided by NIOSH]
• Subjects:
  Asbestos Cells, Cultured Inorganic Chemicals Neoplasms Occupational Health Risk Assessment Risk Factors Safety
• Keywords:
  Analytical-processes Asbestos-products Cancer Cell-biology Cell-cultures Cell-damage Cellular-function Cellular-reactions Exposure-levels Malignancy Proteins Risk-factors

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• ISSN:
  1471-2407
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; 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:
  13
• NIOSHTIC Number:
  nn:20042824
• Citation:
  BMC Cancer 2013 Mar; 13:140
• Email:
  ybao4356@gmail.com
• Federal Fiscal Year:
  2013
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  BMC Cancer
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d45fa6d7768060f2a3b841184156ff2c4ef2bade42516720b2d0145a6481b1d457f943438c4d6ec45ab3580d29fe354aa32e301294410e9fa81bf7c3b9f27644
• Download URL:
  https://stacks.cdc.gov/view/cdc/194925/cdc_194925_DS1.pdf
• File Type:
  [PDF - 1.93 MB ]