TRAIL enhances proteasome inhibitor-induced apoptosis in human malignant pleural mesothelioma cells through promoting caspase activation and Mcl-1 protein cleavage.

Details

• Personal Author:
  Chapman JA ; 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. General resistance to current treatments and steady increase in the incidence necessitate an urgent need for developing new treatments for MPM. Proteasome inhibitors (PIs) have emerged as new promising agents for treating MPM. PIs has been found to be able to induce a moderate apoptosis in human MPM cells through activating the intrinsic apoptosis pathway, which is regulated by the concomitantly elevated Mcl-1 protein. TRAIL is a tumor cell-specific death inducing cytokine which induces apoptosis through activating the extrinsic apoptosis pathway. A recent study has demonstrated that TRAIL enhances PI-induced apoptosis by helping initiate a positive feedback mechanism leading to Mcl-1 protein cleavage in some lung cancer cells. To enhance PI-induced apoptosis in MPM cells, we investigated the effect of TRAIL (10-20 ng/ml) and PI (MGI32, 0.5-1 microM) combination treatment. It was found that TRAIL and PI co-treatment induced a much more significant apoptosis, as was measured by cell viability, DNA damage and protein cleavages, than treatment with either single agent alone in MPM cell lines NCI-H2452, NCI-H2052 and NCI-H28. Using caspase specific inhibitors, we further found that activation of both the intrinsic and extrinsic apoptosis pathways contributed to the combination treatment-induced apoptosis. Moreover, it was found that such apoptosis induction was governed by a positive feedback mechanism which enhanced caspase activations and induced Mcl-1 protein cleavage leading to ensured cell death. Most importantly, we observed that the combination treatment exhibited a preferential toxicity to MPM cells rather than to non-tumorigenic Met-5A mesothelial cells. We thus conclude that TRAIL enhances PI-induced apoptosis in MPM cells, through promoting the positive feedback mechanism-governed caspase activation and Mcl-1 protein cleavage. And, TRAIL and PI combination treatment may therefore represent a new effective therapy for treating MPMs. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Cancer; Lung-cancer; Respiratory-system-disorders; Pulmonary-system-disorders; Cellular-reactions; Therapeutic-agents; Cell-cultures; Cell-function; Cellular-function; Mesothelial-cells; Chemotherapy
• ISSN:
  0197-016X
• Publisher:
  American Association for Cancer Research
• Document Type:
  Text
• Genre:
  Abstract or Summary
• 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
• Pages in Document:
  98
• Volume:
  50
• NIOSHTIC Number:
  nn:20035424
• Citation:
  Proceedings of the American Association for Cancer Research (AACR) 100th Annual Meeting, April 18-22, 2009, Denver, Colorado. Abstract 404. Philadelphia, PA: American Association for Cancer Research, 2009 Apr; 50:98
• CAS Registry Number:
  Asbestos (CAS RN 1332-21-4)
• Federal Fiscal Year:
  2009
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  Proceedings of the American Association for Cancer Research (AACR) 100th Annual Meeting, April 18-22, 2009, Denver, Colorado
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7dc847c09aedf140bc731323e8446b4703641ae07d6ad9e7b7238120dab30b8f7dcaa9b938d34d035f87873a0fe7fec262d5d13dcaf290925445e82b6de3b57d
• Download URL:
  https://stacks.cdc.gov/view/cdc/248030/cdc_248030_DS1.pdf
• File Type:
  [PDF - 168.02 KB ]