Abstract
The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.
Highlights
Cells have evolved intricate regulatory mechanisms to adjust their proteomes in response to intracellular and environmental conditions, allowing for healthy growth and survival [1]
The ubiquitin-proteasome system (UPS) is central to the unfolded protein response (UPR), which is activated when unfolded or misassembled proteins accumulate in the endoplasmic reticulum (ER)
Label-free quantitative proteomic analysis indicates that less than 10% of total cellular proteasomes are bound to ubiquitin-independent activators [55]; recruitment of PA28γ and PA200 to proteasomes is an unexpected consequence of catalytic inhibition, suggesting that their roles in cell biology might have clinical significance, such as in resistance to proteasome inhibition [56]
Summary
Cells have evolved intricate regulatory mechanisms to adjust their proteomes in response to intracellular and environmental conditions, allowing for healthy growth and survival [1]. While the fundamental mechanistic and structural details of the proteasome are still active areas of investigation [16], the use of proteasome inhibitors in clinic has proven to be successful in treating cancer, multiple myeloma (MM) and mantle cell lymphoma (MCL), with the number and types of disease indications growing [17,18,19,20]. While proteasome inhibitors have been successfully employed to treat cancer, where inhibiting uncontrolled cell growth is important, there are other circumstances in which activating the proteasome could be advantageous, including in the treatment of neurodegeneration. In addition to highlighting the current state of proteasome inhibitors in laboratory and clinic, this review will offer perspectives on how to improve the efficacy of current proteasome inhibitors (alone or as combination therapies), directions for developing new UPS inhibitors (including for targets other than the proteasome itself), and fundamental research directions that will enhance proteasome inhibitor development and validation
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