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

• Published in: BMC cancer 2013-03, Vol.13 (1), p.140-140, Article 140
• Main Authors: Yuan, Bao-Zhu, Chapman, Joshua, Ding, Min, Wang, Junzhi, Jiang, Binghua, Rojanasakul, Yon, Reynolds, Steven H
• Format: Article
• Language: English
• Subjects: Analysis; Antimitotic agents; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Blotting, Western; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cells; Cellular biology; Combined Modality Therapy; Drug therapy; Enzymes; Flow Cytometry; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - genetics; Mesothelioma - pathology; Mesothelioma, Malignant; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Pleural Neoplasms - drug therapy; Pleural Neoplasms - genetics; Pleural Neoplasms - pathology; Proteasome Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Tumor Cells, Cultured
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-13-140

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. 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. 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. The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.