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

Our plain-English summary of TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages, by B.Z. Yuan, J. Chapman, M. Ding, et al (BMC Cancer, 2013).

The study

• Authors: B.Z. Yuan, J. Chapman, M. Ding, J. Wang, B. Jiang, Y. Rojanasakul, S.H. Reynolds
• Journal: BMC Cancer
• Published: 2013;13:140
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

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

In plain English

This was a laboratory study of human cancer cells grown in dishes. No patients, animals or asbestos exposure were studied. The authors tested a proteasome inhibitor drug, MG132, and a protein called TRAIL in three malignant pleural mesothelioma cell lines (sarcomatoid, epithelial and biphasic types) and in one non-tumorigenic mesothelial cell line, Met-5A. Used alone, MG132 or TRAIL caused only limited or mild cell death, and each failed in one of the three mesothelioma lines. MG132 alone raised levels of Mcl-1, a protein that protects cells from dying. MG132 combined with TRAIL sharply increased cell death in all three mesothelioma lines. Blocking caspases, enzymes that carry out cell death, reduced this effect. A second proteasome inhibitor, Bortezomib, gave a similar result with TRAIL in the one line where it was tested. Keeping a survival protein called Akt permanently switched on made cells more resistant. The Met-5A cells showed much less cell death. The authors concluded the combination may represent an effective new treatment for this disease. They noted that the reason for its selectivity needs further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on human cell lines
• Who was studied: Three human malignant pleural mesothelioma cell lines bought from ATCC (NCI-H2052, sarcomatoid; NCI-H28, epithelial; NCI-H2452, biphasic or mixed), plus the non-tumorigenic mesothelial cell line Met-5A for comparison. No patients were studied.
• Exposure: Drug treatments, not asbestos. The main treatments were the proteasome inhibitor MG132 (0.5-1 μM), TRAIL (10–20 ng/ml), and the two combined. Bortezomib (30 nM) with 5 ng/ml TRAIL was tested in NCI-H28 cells only. Additional experiments used caspase inhibitors, the PI3K inhibitor LY294002, Mcl-1 silencing, and a constitutively active Akt gene. Asbestos exposure was not studied.
• Main results:
  • MG132 alone caused significant cell death in the NCI-H2452 and NCI-H2052 cell lines, but not in NCI-H28.
  • MG132 alone raised Mcl-1 protein levels in all three mesothelioma cell lines.
  • TRAIL alone (10–20 ng/ml) caused mild cell death in the NCI-H28 and NCI-H2452 cell lines, but not in NCI-H2052.
  • MG132 combined with TRAIL sharply increased cell death in all three mesothelioma cell lines.
  • In NCI-H28 cells given the combination, inhibiting each individual caspase significantly reduced cell death.
  • Bortezomib combined with TRAIL also caused robust cell death in NCI-H28 cells, the only line in which it was tested.
  • In NCI-H2452 cells, a permanently active form of Akt reduced the cell-death signals caused by MG132, by TRAIL, and by the two combined.
  • The fall in activated Akt after the combination treatment was completely blocked by caspase inhibitors.
  • In NCI-H28 cells, neither the PI3K inhibitor LY294002 nor Mcl-1 silencing alone made the cells more sensitive to MG132, but the two together did.
  • The non-tumorigenic Met-5A mesothelial cells showed much less cell death from the MG132 and TRAIL combination than the three mesothelioma cell lines did.
• The authors' conclusion: The authors concluded that combining TRAIL with a proteasome inhibitor may represent an effective new treatment for malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors stated that the mechanism behind the combination's selectivity for mesothelioma cells needs further investigation.
  • The antibodies used could not tell apart the different forms (isoforms) of the Akt protein.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Pleural Mesothelioma, Asbestos Exposure, Mesothelial Cells.

Related studies

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• Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation — Y.J. Lee, Y.J. Lee, et al. (2015)
• Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis — F. Cerruti, G. Jocollè, et al. (2017)
• Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells — B.Z. Yuan, J.A. Chapman, et al. (2008)
• Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells — R. Eguchi, S. Kubo, et al. (2012)
• Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway — K.H. Kim, J.I. Chae, et al. (2016)

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