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

F Cerruti, G Jocollè, C Salio, Laura Oliva, L Paglietti, B Alessandria, S Mioletti, G Donati, G Numico, S Cenci, P Cascio

Research output: Contribution to journalArticle

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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. © 2017 The Author(s).
Original languageEnglish
Article number 17626
JournalScientific Reports
Volume7
Issue number2
DOIs
Publication statusPublished - 2017

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Proteasome Endopeptidase Complex
Apoptosis
Proteasome Inhibitors
Mesothelioma
Ubiquitin
Asbestos
Bortezomib
Malignant Mesothelioma
Epithelium
Clone Cells
Clinical Trials
Neoplasms
Proteins

Cite this

Cerruti, F., Jocollè, G., Salio, C., Oliva, L., Paglietti, L., Alessandria, B., ... Cascio, P. (2017). Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis. Scientific Reports, 7(2), [ 17626]. https://doi.org/10.1038/s41598-017-17977-9

Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis. / Cerruti, F; Jocollè, G; Salio, C; Oliva, Laura; Paglietti, L; Alessandria, B; Mioletti, S; Donati, G; Numico, G; Cenci, S; Cascio, P.

In: Scientific Reports, Vol. 7, No. 2, 17626, 2017.

Research output: Contribution to journalArticle

Cerruti, F, Jocollè, G, Salio, C, Oliva, L, Paglietti, L, Alessandria, B, Mioletti, S, Donati, G, Numico, G, Cenci, S & Cascio, P 2017, 'Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis', Scientific Reports, vol. 7, no. 2, 17626. https://doi.org/10.1038/s41598-017-17977-9
Cerruti, F ; Jocollè, G ; Salio, C ; Oliva, Laura ; Paglietti, L ; Alessandria, B ; Mioletti, S ; Donati, G ; Numico, G ; Cenci, S ; Cascio, P. / Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis. In: Scientific Reports. 2017 ; Vol. 7, No. 2.
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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. {\circledC} 2017 The Author(s).",
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