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Nature Communications Nov 2022Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large...
Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Bortezomib; Proteomics; Apoptosis; Proteasome Endopeptidase Complex; Immunoglobulins; Deubiquitinating Enzymes; Ubiquitin-Specific Proteases
PubMed: 36357400
DOI: 10.1038/s41467-022-34654-2 -
Cells Jun 2021The ubiquitin-proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential... (Review)
Review
The ubiquitin-proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.
Topics: Hematologic Neoplasms; Hematopoiesis; Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Signal Transduction
PubMed: 34206607
DOI: 10.3390/cells10071577 -
Molecules (Basel, Switzerland) Feb 2023Although proteasome inhibitors have emerged as the therapeutic backbone of multiple myeloma treatment, patients often relapse and become drug refractory. The combination...
Although proteasome inhibitors have emerged as the therapeutic backbone of multiple myeloma treatment, patients often relapse and become drug refractory. The combination between proteasome and histone deacetylase inhibitors has shown to be more efficient compared to monotherapy by enhancing the anti-myeloma activity and improving the patient's lifetime expectancy. Hybrid molecules, combining two drugs/pharmacophores in a single molecular entity, offer improved effectiveness by modulating more than one target and circumventing differences in the pharmacokinetic and pharmacodynamic profiles, which are the main disadvantages of combination therapy. Therefore, eleven histone deacetylase-proteasome inhibitor hybrids were synthesized, combining pharmacophores of entinostat and bortezomib. Compound displayed the strongest antiproliferative activity with an IC value of 9.5 nM in the multiple myeloma cells RPMI 8226, 157.7 nM in the same cell line resistant to bortezomib, and 13.1 nM in a 3D spheroid model containing multiple myeloma and mesenchymal stem cells. Moreover, the compound inhibited 33% of histone deacetylase activity when RPMI 8226 cells were treated for 8 h at 10 µM. It also inhibited the proteasome activity with an IC value of 23.6 nM.
Topics: Humans; Bortezomib; Multiple Myeloma; Antineoplastic Agents; Proteasome Endopeptidase Complex; Boronic Acids; Cell Line, Tumor; Neoplasm Recurrence, Local; Proteasome Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Drug Resistance, Neoplasm
PubMed: 36771118
DOI: 10.3390/molecules28031456 -
Biomolecules Dec 2021Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby... (Review)
Review
Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.
Topics: Adult; Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Drug Delivery Systems; Humans; Multiple Myeloma; Proteasome Inhibitors
PubMed: 35053199
DOI: 10.3390/biom12010051 -
Cell Reports. Medicine Sep 2022Although the MAPK pathway is aberrantly activated in triple-negative breast cancers (TNBCs), the clinical outcome of MEK-targeted therapy is still poor. Through a...
Although the MAPK pathway is aberrantly activated in triple-negative breast cancers (TNBCs), the clinical outcome of MEK-targeted therapy is still poor. Through a genome-wide CRISPR-Cas9 library screening, we find that inhibition of PSMG2 sensitizes TNBC cells BT549 and MB468 to the MEK inhibitor AZD6244. Mechanistically, PSMG2 knockdown impairs proteasome function, which in turn activates autophagy-mediated PDPK1 degradation. The PDPK1 degradation significantly enhances AZD6244-induced tumor cell growth inhibition by interrupting the negative feedback signals toward the AKT pathway. Consistently, co-targeting proteasomes and MEK with inhibitors synergistically suppresses tumor cell growth. The autophagy inhibitor chloroquine partially relieves the PDPK1 degradation and reverses the growth inhibition induced by combinatorial inhibition of MEK and proteasome. The combination regimen with the proteasome inhibitor MG132 plus AZD6244 synergistically inhibits tumor growth in a 4T1 xenograft mouse model. In summary, our study not only unravels the mechanism of MEK inhibitor resistance but also provides a combinatorial therapeutic strategy for TNBC in clinics.
Topics: 3-Phosphoinositide-Dependent Protein Kinases; Animals; Autophagy; Cell Line, Tumor; Chaperonins; Chloroquine; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proto-Oncogene Proteins c-akt; Triple Negative Breast Neoplasms
PubMed: 36099919
DOI: 10.1016/j.xcrm.2022.100741 -
Blood May 2022High-dose melphalan supported by autologous transplantation has been the standard of care for eligible patients with newly diagnosed multiple myeloma (MM) for >25 years.... (Review)
Review
High-dose melphalan supported by autologous transplantation has been the standard of care for eligible patients with newly diagnosed multiple myeloma (MM) for >25 years. Several randomized clinical trials have recently reaffirmed the strong position of transplantation in the era of proteasome inhibitors and immunomodulatory drugs combinations, demonstrating a significant reduction of progression or death in comparison with strategies without transplantation. Immunotherapy is currently changing the paradigm of MM management, and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved in the setting of newly diagnosed MM. Quadruplets have become the new standard in transplantation programs, but outcomes remain heterogeneous, with various response depth and duration. The development of sensitive and specific tools for disease prognostication allows the consideration of strategies adaptive to dynamic risk. This review discusses the different options available for the treatment of transplantation-eligible patients with MM in frontline setting.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Melphalan; Multiple Myeloma; Proteasome Inhibitors; Transplantation, Autologous
PubMed: 34788422
DOI: 10.1182/blood.2020008735 -
International Journal of Radiation... Apr 2024Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating... (Review)
Review
Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating evidence suggests that deubiquitinases (DUBs) play a crucial role in regulating cell sensitivity to ionizing radiation. Traditional small-molecule DUB inhibitors have demonstrated radiosensitization effects, and novel deubiquitinase-targeting chimeras (DUBTACs) provide a promising strategy for radiosensitizer development by harnessing the ubiquitin-proteasome system. This review highlights the mechanisms by which DUBs regulate radiosensitivity, including DNA damage repair, the cell cycle, cell death, and hypoxia. Progress on DUB inhibitors and DUBTACs is summarized, and their potential radiosensitization effects are discussed. Developing drugs targeting DUBs appears to be a promising alternative approach to overcoming radioresistance, warranting further research into their mechanisms.
Topics: Humans; Antineoplastic Agents; Proteasome Inhibitors; Neoplasms; Deubiquitinating Enzymes; Radiation Tolerance
PubMed: 38092257
DOI: 10.1016/j.ijrobp.2023.12.003 -
Cells Dec 2021Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called... (Review)
Review
Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers.
Topics: Animals; Humans; Models, Biological; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Subunits
PubMed: 34944095
DOI: 10.3390/cells10123587 -
Scientific Reports Sep 2023Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to...
Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue. Although these observations suggest a pan-breast cancer utility for proteasome inhibitors, our further experiments with breast cancer cell lines and patient-derived xenografts (PDX) pointed to triple-negative breast cancer (TNBC) as the most sensitive subtype to proteasome inhibition. Finally, using TNBC cells, we extended our studies to in vivo xenograft experiments. Our previous work has firmly established a cytoprotective role for the transcription factor NRF1 via its ability to upregulate proteasome genes in response to proteasome inhibition. In further support of this notion, we show here that NRF1 depletion significantly reduced tumor burden in an MDA-MB-231 TNBC xenograft mouse model treated with carfilzomib. Taken together, our results point to TNBC as a particularly vulnerable breast cancer subtype to proteasome inhibition and provide a proof-of-principle for targeting NRF1 as a viable means to increase the efficacy of proteasome inhibitors in TNBC tumors.
Topics: Animals; Humans; Mice; Cytoplasm; Disease Models, Animal; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Triple Negative Breast Neoplasms; NF-E2-Related Factor 1
PubMed: 37739987
DOI: 10.1038/s41598-023-43121-x -
Science Advances Sep 2022The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC)...
The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs). Interrogation of ETC-suppressed MM reveals integrated stress response-dependent suppression of protein translation and ubiquitination, leading to PI resistance. ETC and protein translation gene expression signatures from the CoMMpass trial are down-regulated in patients with poor outcome and relapse, corroborating our in vitro findings. ETC-suppressed MM exhibits up-regulation of the cystine-glutamate antiporter , and analysis of patient single-cell RNA-seq shows that clusters with low ETC gene expression correlate with higher expression. Furthermore, erastin or venetoclax treatment diminishes mitochondrial stress-induced PI resistance. In sum, our work demonstrates that mitochondrial stress promotes PI resistance and underscores the need for implementing combinatorial regimens in MM cognizant of mitochondrial metabolic state.
Topics: Antiporters; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cystine; Glutamates; Humans; Multiple Myeloma; Proteasome Inhibitors; Proto-Oncogene Proteins c-bcl-2; Sulfonamides
PubMed: 36170375
DOI: 10.1126/sciadv.abq5575