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.
Highlights
The 26S proteasome is an ATP-dependent protease complex abundantly expressed in eukaryotic cells, responsible for the regulated hydrolysis of most cellular proteins[1]
In an effort aimed at verifying whether different malignant pleural mesothelioma (MPM) cell lines display differential sensitivity to apoptosis triggered by proteasome inhibition, we initially tested the biological effects of bortezomib on a panel of four human MPM clones
We demonstrated that the aforementioned MPM lines are characterized by a well-defined differential sensitivity/resistance to bortezomib and are suitable for investigating the molecular mechanisms responsible for the different susceptibility of MPM cells to apoptosis caused by proteasome inhibition
Summary
The 26S proteasome is an ATP-dependent protease complex abundantly expressed in eukaryotic cells, responsible for the regulated hydrolysis of most cellular proteins[1]. 20S particle, where polypeptides get hydrolyzed, associated with the 19S regulatory particles, responsible for recognizing, unfolding, and translocating polyubiquitinated proteins into the inner degradative chamber of the 20S2. This is a ~700 kDa cylindrical macromolecular machine formed by four overlapping heptameric rings, consisting of α (the outer rings) or β (the inner rings) subunits[3]. Since proteasome inhibitors (PIs) induce adaptive and maladaptive responses (e.g. the unfolded protein and heat-shock responses), showing previously unpredicted specificity against certain tumor cells, they became the paradigm of negative proteostasis regulators in cancer therapy[7]. ® clinical trials allowed the rapid approval of the modified boronic dipeptide bortezomib (Btz, PS-341 or Velcade )
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