The dichotomous role of immunoproteasome in cancer: Friend or foe?

Chen, Boya; Zhu, Hongqing; Yang, Bo; Cao, Ji

doi:10.1016/j.apsb.2022.11.005

Cited by 7 publications

(7 citation statements)

References 115 publications

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“…The clinical implication of the observed MKIs effects might be dichotomous. Indeed, upregulation of constitutive and non-constitutive proteasomes, which is frequently observed in cancer, could be both beneficial and detrimental for the tumor ( Rouette et al, 2016 ; Leister et al, 2021 ; Chen et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

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Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

Burov,

Grigorieva,

Lebedev

et al. 2024

Front. Mol. Biosci.

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Introduction: Proteasomes are multi-subunit protein complexes responsible for protein degradation in cells. Immunoproteasomes and intermediate proteasomes (together non-constitutive proteasomes) are specific forms of proteasomes frequently associated with immune response, antigen presentation, inflammation and stress. Expression of non-constitutive proteasome subunits has a prognostic value in several types of cancer. Thus, factors that modulate non-constitutive proteasome expression in tumors are of particular interest. Multikinase inhibitors (MKIs) demonstrate promising results in treatment of cancer. At the same time, their immunomodulatory properties and effects on non-constitutive proteasome expression in colorectal cancer cells are poorly investigated.Methods: Proteasome subunit expression in colorectal cancer was evaluated by bioinformatic analysis of available datasets. Two colorectal cancer cell lines, expressing fluorescent non-constitutive proteasomes were treated with multikinase inhibitors: regorafenib and sorafenib. The proteasome subunit expression was assessed by real-time PCR, Western blotting and flow cytometry. The proteasome activity was studied using proteasome activity-based probe and fluorescent substrates. Intracellular proteasome localization was revealed by confocal microscopy. Reactive oxygen species levels following treatment were determined in cells. Combined effect of proteasome inhibition and treatment with MKIs on viability of cells was estimated.Results: Expression of non-constitutive proteasomes is increased in BRAF-mutant colorectal tumors. Regorafenib and sorafenib stimulated the activity and synthesis of non-constitutive proteasomes in examined cell lines. MKIs induced oxidative stress and redistribution of proteasomes within cells. Sorafenib stimulated formation of cytoplasmic aggregates, containing proteolyticaly active non-constitutive proteasomes, while regorafenib had no such effect. MKIs caused no synergistic action when were combined with the proteasome inhibitor.Discussion: Obtained results indicate that MKIs might affect the crosstalk between cancer cells and immune cells via modulation of intracellular proteasome pool. Observed phenomenon should be considered when MKI-based therapy is applied.

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Section: Discussionmentioning

confidence: 99%

“…On the other hand, non-constitutive proteasomes are involved in degradation of tumor suppressor proteins ( Chen et al, 2023 ). Along these lines, upregulation of PSMB9 is an unfavorable prognostic marker in renal cancer.…”

Section: Discussionmentioning

confidence: 99%

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

Burov,

Grigorieva,

Lebedev

et al. 2024

Front. Mol. Biosci.

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“…Despite this promise, the design and development of vaccine epitopes that provide robust priming of cytotoxic T cells has thus far proved difficult. A key challenge is thought to be due to insufficient epitope processing and presentation, which leads to reduced vaccine efficacy and has thus far precluded FDA approvals for T cell vaccines 5 .…”

Section: Main Textmentioning

confidence: 99%

Design of Cytotoxic T Cell Epitopes by Machine Learning of Human Degrons

Truex,

Mohapatra,

Melo

et al. 2023

Preprint

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Antigen processing is critical for producing epitope peptides that are presented by HLA molecules for T cell recognition. Therapeutic vaccines aim to harness these epitopes for priming cytotoxic T cell responses against cancer and pathogens, but insufficient processing often reduces vaccine efficacy through limiting the quantity of epitopes released. Here, we set out to improve antigen processing by harnessing protein degradation signals called degrons from the ubiquitin-proteasome system. We used machine learning to generate a computational model that ascribes a proteasomal degradation score between 0 and 100. Epitope peptides with varying degron activities were synthesized and translocated into cells using nontoxic anthrax proteins: protective antigen (PA) and the N-terminus of lethal factor (LFN). Immunogenicity studies revealed epitope sequences with a low score (<25) show pronounced T-cell activation but epitope sequences with a higher score ( >75) provide limited activation. This work sheds light on the sequence-activity relationships between proteasomal degradation and epitope immunogenicity, through conserving the epitope region but varying the flanking sequence. We anticipate that future efforts to incorporate proteasomal degradation signals into vaccine designs will lead to enhanced cytotoxic T cell priming by vaccine therapeutics in clinical settings.

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“…Despite this promise, the design and development of vaccine epitopes that provide robust priming of cytotoxic T cells has thus far proved difficult. One key challenge is thought to be due to insufficient epitope processing and presentation, which leads to reduced vaccine efficacy …”

Section: Introductionmentioning

confidence: 99%

“…One key challenge is thought to be due to insufficient epitope processing and presentation, which leads to reduced vaccine efficacy. 5 Developing an antigen-specific vaccine typically includes sequence characterization of a tumor, bacterial, or viral protein, followed by the design of one or more immunogenic epitopes for the vaccine formulation. The epitope sequence typically comprises 8−9 amino acids for cross-presentation and additional flanking amino acids to limit uncontrolled proteolysis.…”

Section: ■ Introductionmentioning

confidence: 99%

Design of Cytotoxic T Cell Epitopes by Machine Learning of Human Degrons

Truex,

Mohapatra,

Melo

et al. 2024

ACS Cent. Sci.

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Antigen processing is critical for therapeutic vaccines to generate epitopes for priming cytotoxic T cell responses against cancer and pathogens, but insufficient processing often limits the quantity of epitopes released. We address this challenge using machine learning to ascribe a proteasomal degradation score to epitope sequences. Epitopes with varying scores were translocated into cells using nontoxic anthrax proteins. Epitopes with a low score show pronounced immunogenicity due to antigen processing, but epitopes with a high score show limited immunogenicity. This work sheds light on the sequence–activity relationships between proteasomal degradation and epitope immunogenicity. We anticipate that future efforts to incorporate proteasomal degradation signals into vaccine designs will lead to enhanced cytotoxic T cell priming by these vaccines in clinical settings.

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The dichotomous role of immunoproteasome in cancer: Friend or foe?

Cited by 7 publications

References 115 publications

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

Design of Cytotoxic T Cell Epitopes by Machine Learning of Human Degrons

Design of Cytotoxic T Cell Epitopes by Machine Learning of Human Degrons

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