title: TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages.
abstract: 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 TNFα-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 μM 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.
  
  
  CONCLUSIONS
  The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.
authors.forename: Bao-Zhu
authors.initials: BZ
authors.lastname: Yuan
authors.forename: Joshua
authors.initials: J
authors.lastname: Chapman
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.forename: Junzhi
authors.initials: J
authors.lastname: Wang
authors.forename: Binghua
authors.initials: B
authors.lastname: Jiang
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
authors.forename: Steven H
authors.initials: SH
authors.lastname: Reynolds
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt