Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis

Our plain-English summary of Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis, by F. Cerruti, G. Jocollè, C. Salio, et al (Scientific Reports, 2017).

The study

• Authors: F. Cerruti, G. Jocollè, C. Salio, L. Oliva, L. Paglietti, B. Alessandria, S. Mioletti, G. Donati, G. Numico, S. Cenci, P. Cascio
• Journal: Scientific Reports
• Published: 2017;7(1):17626
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Based on promising results in preclinical models, clinical trials have been performed to evaluate the efficacy of the first-in-class proteasome inhibitor bortezomib towards malignant pleural mesothelioma (MPM), an aggressive cancer arising from the mesothelium of the serous cavities following exposure to asbestos. Unexpectedly, only minimal therapeutic benefits were observed, thus implicating that MPM harbors inherent resistance mechanisms. Identifying the molecular bases of this primary resistance is crucial to develop novel pharmacologic strategies aimed at increasing the vulnerability of MPM to bortezomib. Therefore, we assessed a panel of four human MPM lines with different sensitivity to bortezomib, for functional proteasome activity and levels of free and polymerized ubiquitin. We found that highly sensitive MPM lines display lower proteasome activity than more bortezomib-resistant clones, suggesting that reduced proteasomal capacity might contribute to the intrinsic susceptibility of mesothelioma cells to proteasome inhibitors-induced apoptosis. Moreover, MPM equipped with fewer active proteasomes accumulated polyubiquitinated proteins, at the expense of free ubiquitin, a condition known as proteasome stress, which lowers the cellular apoptotic threshold and sensitizes mesothelioma cells to bortezomib-induced toxicity as shown herein. Taken together, our data suggest that an unfavorable load-versus-capacity balance represents a critical determinant of primary apoptotic sensitivity to bortezomib in MPM.

In plain English

This was a laboratory study of four human malignant pleural mesothelioma (MPM) cell lines grown in culture (MM98, REN, MMB and MSTO-211H). It did not study people or asbestos exposure. The authors wanted to understand why MPM cells differ in how they respond to bortezomib, a drug that blocks the proteasome, the cell's main protein-disposal machinery. After 48 hours of treatment, the dose needed to produce half the maximum cell-death effect (EC50) was about 17 nM for MM98, 22 nM for REN, 33 nM for MMB and 60 nM for MSTO-211H. The more sensitive lines had lower proteasome activity. They also had less free ubiquitin, a small protein used to tag other proteins for disposal, and a larger build-up of tagged proteins. This build-up is a condition called proteasome stress. More build-up went with lower proteasome activity and with greater sensitivity to bortezomib. The authors concluded that an imbalance between the protein-disposal workload and the cells' disposal capacity is a critical determinant of sensitivity to bortezomib in MPM. They suggested that measuring proteasome stress might help predict patients' response. They said further studies are needed to understand the mechanisms.

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) study of human mesothelioma cell lines
• Who was studied: Four human malignant pleural mesothelioma cell lines (MM98, REN, MMB, MSTO-211H), provided by researchers at the University of Milan and the University of Hawaii. No human subjects.
• Exposure: The proteasome-inhibiting drug bortezomib at increasing concentrations (nanomolar range) for 48 hours. Asbestos exposure was not studied.
• Main results:
  • All four lines underwent dose-dependent cell death, but sensitivity differed. EC50 values (average of 3 experiments, plus or minus standard error) were: MM98 16.9 plus or minus 1.7 nM, REN 22.1 plus or minus 1.4 nM, MMB 33.4 plus or minus 2.0 nM and MSTO-211H 60.1 plus or minus 8.6 nM.
  • Across the four lines, higher chymotrypsin-like and trypsin-like proteasome activities went with greater resistance to bortezomib. No clear correlation was established for the minor caspase-like activity.
  • Levels of individual proteasome subunits varied between the lines in an uncoordinated way.
  • The more sensitive MM98 and REN lines had significantly less free ubiquitin than the MMB and MSTO-211H lines, and they had accumulated polyubiquitin chains.
  • Microscopy measurements of tagged (polyubiquitinated) proteins correlated negatively both with proteasome activity and with the EC50 for bortezomib. In other words, lines with more build-up had lower proteasome activity and needed lower doses.
• The authors' conclusion: The authors concluded that an unfavorable balance between protein-disposal workload and proteasome capacity is a critical determinant of sensitivity to bortezomib in MPM cells. They suggested that assessing proteasome stress and capacity in MPM patients might help predict response to bortezomib.
• Limitations the authors state:
  • The authors stated that further studies are needed to fully understand the mechanisms behind the imbalance in MPM.
  • The authors noted that measured levels of α-subunits may not reflect assembled, working proteasomes.

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: Pleural Mesothelioma, Apoptosis, Clinical Trial, Mesothelium, Serous Cavities, Mesothelioma.

Related studies

• Withaferin A inhibits the proteasome activity in mesothelioma in vitro and in vivo — H. Yang, Y. Wang, et al. (2012)
• TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages — B.Z. Yuan, J. Chapman, et al. (2013)
• Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines — Y. Wang, A.K. Rishi, et al. (2010)
• Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma — D. Xu, S.Q. Liang, et al. (2018)
• Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors — R. Bahleda, M.C. Le Deley, et al. (2018)
• Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis — W. Aung, S. Hasegawa, et al. (2007)

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