Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells

Our plain-English summary of Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells, by B.Z. Yuan, J.A. Chapman, S.H. Reynolds (Translational Oncology, 2008).

The study

• Authors: B.Z. Yuan, J.A. Chapman, S.H. Reynolds
• Journal: Translational Oncology
• Published: 2008;1(3):129-40
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy tightly associated with asbestos exposure. The increasing incidence of MPM and its resistance to all therapeutic modalities necessitate an urgent development of new treatments for MPM. Proteasome inhibitors (PIs) have emerged as promising agents for treating human cancers that are refractory to current chemotherapies. In this study, we characterized MG132, a commonly used PI, for its proapoptotic and anti-invasion activities in NCI-H2452 and NCI-H2052 human thoracic MPM cell lines to determine the therapeutic effect of PIs on MPM. We found that as low as 0.5 microM MG132 caused a significant apoptosis in both cell lines as evidenced by DNA damage, cleavage of poly ADP-ribose polymerase and caspases 3, 7, and 9, and mitochondrial release of Smac/DIABLO and Cytochrome c. Mitochondrial caspase activation was found to be the underlying mechanism of the MG132-induced apoptosis. Mcl-1, among the Bcl-2 and IAP (inhibitor of apoptosis protein) antiapoptotic family proteins tested, was proved to be a major inhibitor of the MG132-induced apoptosis in MPM cells. Meanwhile, subapoptotic doses of MG132 inhibited the invasion of both MPM cell lines through reducing Rac1 activity. These observations demonstrate that MG132 possesses proapoptotic and anti-invasion activities in human MPM cells, therefore encouraging further investigations on the value of PIs for treating MPM.

In plain English

This laboratory study tested a drug called MG132, a proteasome inhibitor, on two human malignant pleural mesothelioma cell lines (NCI-H2052 and NCI-H2452) grown in culture. It did not study asbestos exposure or patients. At doses above 0.25 micromolar, MG132 slowed cell growth in both cell lines. Above 0.5 micromolar it caused significant cell death, more strongly in NCI-H2452 cells. The authors reported that this was apoptosis (programmed cell death). It depended on enzymes called caspases, because caspase blockers reduced it, and it involved the release of proteins from the cells' mitochondria. MG132 also raised the level of a protective protein, Mcl-1. When Mcl-1 was silenced, NCI-H2052 cells died more readily from MG132. Lower doses (0.0625 to 0.125 micromolar), which did not affect cell viability, reduced the cells' ability to invade through a gel barrier in a dose-dependent way. The authors linked this to reduced activity of a protein called Rac1. The authors concluded that MG132 may represent a promising new treatment of mesothelioma, based on these cell experiments.

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) cell-culture experiment
• Who was studied: Two commercially obtained human malignant pleural mesothelioma cell lines, NCI-H2052 and NCI-H2452. A human non-small cell lung carcinoma cell line, NCI-H358, was used as a comparison in one test. No people were studied.
• Exposure: No asbestos exposure was studied. The cells were treated with the proteasome inhibitor drug MG132: 0.25 to 2 micromolar in the cell-death experiments, and lower 'subapoptotic' doses of 0.0625 to 0.125 micromolar in the invasion experiments.
• Main results:
  • In both cell lines, MG132 above 0.25 micromolar inhibited cell growth over 4 days. Above 0.5 micromolar it caused significant cell death, with higher potency in NCI-H2452 cells.
  • Most cells of both cell lines died 72 hours after exposure to more than 1 micromolar MG132.
  • In NCI-H2452 cells, caspase inhibitors significantly suppressed MG132-induced cell death. The authors took this as showing the apoptosis was caspase-dependent.
  • In both cell lines, MG132 caused mitochondrial release of Smac (more abundant) and Cytochrome c (less abundant) into the cytosol.
  • MG132 did not change Bcl-2 or Bcl-XL levels but caused a significant, dose-dependent rise in the long form of the Mcl-1 protein.
  • In NCI-H2052 cells, silencing Mcl-1 (but not XIAP) with siRNA enhanced MG132-induced cell death.
  • Subapoptotic doses of MG132 (0.0625 to 0.125 micromolar) did not affect viability or mobility of either cell line.
  • These same subapoptotic doses significantly inhibited invasion through Matrigel in both cell lines, in a dose-dependent manner.
  • A Src kinase inhibitor (10 micromolar) did not inhibit invasion of either mesothelioma cell line. It did reduce migration of the NCI-H358 lung cancer cells.
  • In NCI-H2452 cells, subapoptotic MG132 significantly reduced active (GTP-bound) Rac1, but not RhoA or Cdc42.
  • In NCI-H2452 cells, a permanently active Rac1 mutant (Rac1-G12V) significantly reduced MG132's inhibition of invasion.
• The authors' conclusion: The authors concluded that MG132 may represent a promising new treatment of malignant pleural mesothelioma, because in these cell lines it induced apoptosis and inhibited invasion.
• Limitations the authors state:
  • The authors stated that Rac1 is not the only target through which MG132 inhibits mesothelioma cell invasion.

Topics

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

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