Abstract
Inhibitors of the 20S proteasome such as bortezomib are cytotoxic to tumor cells and have been proven to be valuable for the clinical management of multiple myeloma. The therapeutic efficacy of bortezomib is, however, hampered by the emergence of acquired resistance. Available data suggest that blocking proteasome activity at the level of proteasome-associated deubiquitinases (DUBs) provides a mechanism to overcome resistance to bortezomib and also to other cancer therapies. The small molecule b-AP15 is an inhibitor of proteasome-associated DUB activity that induces both proteotoxic stress and increases in the levels of reactive oxygen species (ROS) in tumor cells. Antioxidants have been shown to decrease apoptosis induction by b-AP15 and we here addressed the question of the mechanism of redox perturbation by this compound. We show that oxidative stress induction by b-AP15 is abrogated in cells deprived of mitochondrial DNA (ρ 0 cells). We also show associations between the level of proteotoxic stress, the degree of mitochondrial dysfunction, and the extent of induction of hemeoxygenase-1 (HO-1), a target of the redox-regulated Nrf-2 transcription factor. Decreased expression of COX5b (cytochrome c oxidase subunit 5b) and TOMM34 (translocase of outer mitochondrial membrane 34) was observed in b-AP15-treated cells. These findings suggest a mitochondrial origin of the increased levels of ROS observed in cells exposed to the DUB inhibitor b-AP15.
Highlights
Aberrant accumulation of misfolded or damaged proteins is associated with reduced cell survival [1]
We have previously reported that b-AP15, an inhibitor of proteasomeassociated deubiquitinases, generates both proteotoxic stress and oxidative stress [22, 24, 26, 27] and induces mitochondrial dysfunction [42]
Previous reports have demonstrated induction of both strong oxidative stress and proteotoxicity by b-AP15 [22, 27, 61] and showed evidence of mitochondrial toxicity [42]. These findings led to the hypothesis that oxidative stress induction by this class of compounds is mechanistically linked to mitochondrial dysfunction
Summary
Aberrant accumulation of misfolded or damaged proteins is associated with reduced cell survival [1]. Protein quality control is primarily mediated by the ubiquitin-proteasome system (UPS), the major eukaryotic proteolytic pathway, and is essential for cell viability [2, 3]. The proteasome degrades the bulk of cellular protein and is instrumental to the regulation of essential cellular processes such as cell cycle progression [4,5,6,7]. Misfolded, damaged, or temporally regulated proteins are marked for removal by the destruction tag ubiquitin that signals traffic to the proteasome for degradation. Under conditions of proteasome inhibition, misfolded proteins accumulate in tumor cells, resulting in pleiotropic effects such as induction of cytosolic chaperones, endoplasmic reticulum (ER) stress, and oxidative stress [12,13,14]
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