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American Journal of Physiology. Cell... Mar 2020Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system... (Review)
Review
Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs.
Topics: Animals; Antineoplastic Agents; Autophagy; Endoplasmic Reticulum Stress; Humans; Multiple Myeloma; Proteasome Inhibitors
PubMed: 31875696
DOI: 10.1152/ajpcell.00286.2019 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Dec 2019Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression... (Review)
Review
Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.
Topics: Proteasome Endopeptidase Complex; Proteasome Inhibitors; Research; Structure-Activity Relationship; T-Lymphocytes
PubMed: 31955545
DOI: 10.3785/j.issn.1008-9292.2019.12.15 -
Frontiers in Immunology 2022Psoriasis is an autoimmune skin disease associated with multiple comorbidities. The immunoproteasome is a special form of the proteasome expressed in cells of...
INTRODUCTION
Psoriasis is an autoimmune skin disease associated with multiple comorbidities. The immunoproteasome is a special form of the proteasome expressed in cells of hematopoietic origin.
METHODS
The therapeutic use of ONX 0914, a selective inhibitor of the immunoproteasome, was investigated in mice, which spontaneously develop psoriasis-like symptoms, and in the imiquimod murine model.
RESULTS
In both models, treatment with ONX 0914 significantly reduced skin thickness, inflammation scores, and pathological lesions in the analyzed skin tissue. Furthermore, immunoproteasome inhibition normalized the expression of several pro-inflammatory genes in the ear and significantly reduced the inflammatory infiltrate, accompanied by a significant alteration in the αβ and γδ T cell subsets.
DISCUSSION
ONX 0914 ameliorated psoriasis-like symptoms in two different murine psoriasis models, which supports the use of immunoproteasome inhibitors as a therapeutic treatment in psoriasis.
Topics: Mice; Animals; Proteasome Inhibitors; Psoriasis; Skin; Inflammation; Autoimmune Diseases
PubMed: 36591277
DOI: 10.3389/fimmu.2022.1075615 -
Chembiochem : a European Journal of... Jul 2019Cells need to synthesize and degrade proteins consistently. Maintaining a balanced level of protein in the cell requires a carefully controlled system and significant... (Review)
Review
Cells need to synthesize and degrade proteins consistently. Maintaining a balanced level of protein in the cell requires a carefully controlled system and significant energy. Degradation of unwanted or damaged proteins into smaller peptide units can be accomplished by the proteasome. The proteasome is composed of two main subunits. The first is the core particle (20S CP), and within this core particle are three types of threonine proteases. The second is the regulatory complex (19S RP), which has a myriad of activities including recognizing proteins marked for degradation and shuttling the protein into the 20S CP to be degraded. Small-molecule inhibitors of the 20S CP have been developed and are exceptional treatments for multiple myeloma (MM). 20S CP inhibitors disrupt the protein balance, leading to cellular stress and eventually to cell death. Unfortunately, the 20S CP inhibitors currently available have dose-limiting off-target effects and resistance can be acquired rapidly. Herein, we discuss small molecules that have been discovered to interact with the 19S RP subunit or with a protein closely associated with 19S RP activity. These molecules still elicit their toxicity by preventing the proteasome from degrading proteins, but do so through different mechanisms of action.
Topics: Adenosine Triphosphatases; Animals; Deubiquitinating Enzymes; Humans; Mice; Molecular Chaperones; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 30740849
DOI: 10.1002/cbic.201900017 -
Drug Design, Development and Therapy 2020Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful... (Review)
Review
Proteasome is vital for intracellular protein homeostasis as it eliminates misfolded and damaged protein. Inhibition of proteasome has been validated as a powerful strategy for anti-cancer therapy, and several drugs have been approved for treatment of multiple myeloma. Recent studies indicate that proteasome has potent therapeutic effects on a variety of diseases besides cancer, including parasite infectious diseases, bacterial/fungal infections diseases, neurodegenerative diseases and autoimmune diseases. In this review, recent developments of proteasome inhibitors for various diseases and related structure activity relationships are going to be summarized.
Topics: Animals; Antineoplastic Agents; Autoimmune Diseases; Drug Therapy; Humans; Infections; Neoplasms; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Structure-Activity Relationship
PubMed: 33116419
DOI: 10.2147/DDDT.S265793 -
Cancer Research Communications Mar 2023Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of...
UNLABELLED
Multiple myeloma is characterized by clonal proliferation of plasma cells that accumulate preferentially in the bone marrow (BM). The tumor microenvironment is one of the leading factors that promote tumor progression. Neutrophils and monocytes are a major part of the BM tumor microenvironment, but the mechanism of their contribution to multiple myeloma progression remains unclear. Here, we describe a novel mechanism by which S100A8/S100A9 proteins produced by BM neutrophils and monocytes promote the expansion of megakaryocytes supporting multiple myeloma progression. S100A8/S100A9 alone was not sufficient to drive megakaryopoiesis but markedly enhanced the effect of thrombopoietin, an effect that was mediated by Toll-like receptor 4 and activation of the STAT5 transcription factor. Targeting S100A9 with tasquinimod as a single agent and in combination with lenalidomide and with proteasome inhibitors has potent antimyeloma effect that is at least partly independent of the adaptive immune system. This newly identified axis of signaling involving myeloid cells and megakaryocytes may provide a new avenue for therapeutic targeting in multiple myeloma.
SIGNIFICANCE
We identified a novel mechanism by which myeloid cells promote myeloma progression independently of the adaptive immune system. Specifically, we discovered a novel role of S100A8/S100A9, the most abundant proteins produced by neutrophils and monocytes, in regulation of myeloma progression via promotion of the megakaryocyte expansion and angiogenesis. Tasquinimod, an inhibitor of S100A9, has potent antimyeloma effects as a single agent and in combination with lenalidomide and with proteasome inhibitors.
Topics: Humans; Multiple Myeloma; Megakaryocytes; Lenalidomide; Proteasome Inhibitors; Calgranulin B; Calgranulin A; Tumor Microenvironment
PubMed: 36923707
DOI: 10.1158/2767-9764.CRC-22-0368 -
Frontiers in Immunology 2023Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors... (Review)
Review
Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.
Topics: Animals; Humans; Multiple Myeloma; Proteasome Inhibitors; Cell Line, Tumor; T-Lymphocytes; Exportin 1 Protein
PubMed: 37954586
DOI: 10.3389/fimmu.2023.1275329 -
Blood Cancer Journal Sep 2023Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity,...
Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61-78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.
Topics: Humans; Aged; Multiple Myeloma; Proteasome Inhibitors; Quality of Life; Molecular Targeted Therapy; Bortezomib
PubMed: 37726298
DOI: 10.1038/s41408-023-00912-9 -
Frontiers in Oncology 2021The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by... (Review)
Review
The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.
PubMed: 34858819
DOI: 10.3389/fonc.2021.740796 -
Viruses Sep 2023Although the involvement of the ubiquitin-proteasome system (UPS) in several coronavirus-productive infections has been reported, whether the UPS is required for...
Although the involvement of the ubiquitin-proteasome system (UPS) in several coronavirus-productive infections has been reported, whether the UPS is required for infectious bronchitis virus (IBV) and porcine epidemic diarrhea virus (PEDV) infections is unclear. In this study, the role of UPS in the IBV and PEDV life cycles was investigated. When the UPS was suppressed by pharmacological inhibition at the early infection stage, IBV and PEDV infectivity were severely impaired. Further study showed that inhibition of UPS did not change the internalization of virus particles; however, by using R18 and DiOC-labeled virus particles, we found that inhibition of UPS prevented the IBV and PEDV membrane fusion with late endosomes or lysosomes. In addition, proteasome inhibitors blocked the degradation of the incoming viral protein N, suggesting the uncoating process and genomic RNA release were suppressed. Subsequently, the initial translation of genomic RNA was blocked. Thus, UPS may target the virus-cellular membrane fusion to facilitate the release of incoming viruses from late endosomes or lysosomes, subsequently blocking the following virus uncoating, initial translation, and replication events. Similar to the observation of proteasome inhibitors, ubiquitin-activating enzyme E1 inhibitor PYR-41 also impaired the entry of IBV, enhanced the accumulation of ubiquitinated proteins, and depleted mono-ubiquitin. In all, this study reveals an important role of UPS in coronavirus entry by preventing membrane fusion and identifies UPS as a potential target for developing antiviral therapies for coronavirus.
Topics: Animals; Swine; Proteasome Endopeptidase Complex; Cell Line; Ubiquitin; Coronavirus; Proteasome Inhibitors; Membrane Fusion; Coronavirus Infections; Endosomes; Porcine epidemic diarrhea virus; RNA; Virus Replication
PubMed: 37896778
DOI: 10.3390/v15102001