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Cancers
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Targeting Mechanisms of Protein Degradation for Cancer Therapy
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Targeting Mechanisms of Protein Degradation for Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 18218

Special Issue Editor

Prof. Dr. Jennifer S. Carew

E-Mail Website
Guest Editor
Department of Medicine, Division of Translational Medicine, University of Arizona Cancer Center, Tucson, AZ, USA
Interests: autophagy; NEDD8-mediated protein turnover; experimental therapeutics; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Timed protein degradation is an essential component of maintaining cellular homeostasis. However, this process frequently becomes dysregulated during oncogenesis and malignant progression. Aberrant protein turnover contributes to poor outcomes and drug resistance in a number of forms of cancer. The disrupted protein homeostasis in malignant cells creates an opportunity for selective, targeted therapeutic approaches based on the specific alterations in the protein degradation machinery that affect individual tumor types. The proof of concept that antagonizing dysregulated protein turnover yields anticancer benefits was first demonstrated with the proteasome inhibitor bortezomib, which became the first drug with this specific mechanism of action to ultimately earn FDA approval. The success of bortezomib prompted the development of 2nd-generation proteasome inhibitors as well as many other new agents that more specifically target key regulators of protein turnover. This Special Issue will focus on current approaches to selectively target mechanisms of protein degradation for cancer therapy.

Prof. Dr. Jennifer S. Carew
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein degradation
  • proteasome inhibitor
  • cancer therapy

Published Papers (6 papers)

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Research

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17 pages, 3926 KiB  
Article
Synthesis and Biological Activity of a VHL-Based PROTAC Specific for p38α
by Mónica Cubillos-Rojas, Guillem Loren, Yusuf Z. Hakim, Xavier Verdaguer, Antoni Riera and Angel R. Nebreda
Cancers 2023, 15(3), 611; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030611 - 18 Jan 2023
Cited by 3 | Viewed by 2399
Abstract
We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide [...] Read more.
We report a series of small molecule proteolysis-targeting chimeras (PROTACs) that target the protein kinase p38α for degradation. These PROTACs are based on a ligand of the VHL E3 ubiquitin ligase, which is linked to an ATP competitive inhibitor of p38α. We provide evidence that these compounds can induce the specific degradation of p38α, but not p38β and other related kinases, at nanomolar concentrations in several mammalian cell lines. We also show that the p38α-specific PROTACs are soluble in aqueous solutions and therefore suitable for their administration to mice. Systemic administration of the PROTACs induces p38α degradation only in the liver, probably due to the PROTAC becoming inactivated in that organ, but upon local administration the PROTACs induce p38α degradation in mammary tumors. Our compounds provide an alternative to traditional chemical inhibitors for targeting p38α signaling in cultured cells and in vivo. Full article
(This article belongs to the Special Issue Targeting Mechanisms of Protein Degradation for Cancer Therapy)
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17 pages, 3094 KiB  
Article
Second Generation Small Molecule Inhibitors of Gankyrin for the Treatment of Pediatric Liver Cancer
by Amber M. D’Souza, Manu Gnanamony, Maria Thomas, Peter Hanley, Dipti Kanabar, Pedro de Alarcon, Aaron Muth and Nikolai Timchenko
Cancers 2022, 14(13), 3068; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133068 - 22 Jun 2022
Cited by 1 | Viewed by 1697
Abstract
Background: Gankyrin, a member of the 26S proteasome, is an overexpressed oncoprotein in hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). Cjoc42 was the first small molecule inhibitor of Gankyrin developed; however, the IC50 values of >50 μM made them unattractive for clinical use. [...] Read more.
Background: Gankyrin, a member of the 26S proteasome, is an overexpressed oncoprotein in hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). Cjoc42 was the first small molecule inhibitor of Gankyrin developed; however, the IC50 values of >50 μM made them unattractive for clinical use. Second-generation inhibitors demonstrate a stronger affinity toward Gankyrin and increased cytotoxicity. The aim of this study was to characterize the in vitro effects of three cjoc42 derivatives. Methods: Experiments were performed on the HepG2 (HBL) and Hep3B (pediatric HCC) cell lines. We evaluated the expression of TSPs, cell cycle markers, and stem cell markers by Western blotting and/or real-time quantitative reverse transcription PCR. We also performed apoptotic, synergy, and methylation assays. Results: The treatment with cjoc42 derivatives led to an increase in TSPs and a dose-dependent decrease in the stem cell phenotype in both cell lines. An increase in apoptosis was only seen with AFM-1 and -2 in Hep3B cells. Drug synergy was seen with doxorubicin, and antagonism was seen with cisplatin. In the presence of cjoc42 derivatives, the 20S subunit of the 26S proteasome was more available to transport doxorubicin to the nucleus, leading to synergy. Conclusion: Small-molecule inhibitors for Gankyrin are a promising therapeutic strategy, especially in combination with doxorubicin. Full article
(This article belongs to the Special Issue Targeting Mechanisms of Protein Degradation for Cancer Therapy)
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Review

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24 pages, 1350 KiB  
Review
Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies
by Anna Wolska-Washer and Piotr Smolewski
Cancers 2022, 14(15), 3778; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153778 - 03 Aug 2022
Cited by 7 | Viewed by 3702
Abstract
Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding [...] Read more.
Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studies have led to the development of proteasome inhibitors, which have advanced into drugs (such as bortezomib) used in the treatment of certain hematological tumors, including multiple myeloma. New therapeutic options have been studied making use of the so-called proteolysis-targeting chimeras (PROTACs), that bind desired proteins with a linker that connects them to an E3 ubiquitin ligase, resulting in proteasomal-targeted degradation. This review examines the mechanisms of protein degradation in the cells of the hematopoietic system, explains the role of dysfunctional protein degradation in the pathogenesis of hematological malignancies, and discusses the current and future advances of therapies targeting these pathways, based on an extensive search of the articles and conference proceedings from 2005 to April 2022. Full article
(This article belongs to the Special Issue Targeting Mechanisms of Protein Degradation for Cancer Therapy)
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13 pages, 867 KiB  
Review
Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer
by Trace M. Jones, Jennifer S. Carew, Julie E. Bauman and Steffan T. Nawrocki
Cancers 2021, 13(13), 3250; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133250 - 29 Jun 2021
Cited by 5 | Viewed by 3093
Abstract
Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that [...] Read more.
Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that target novel pathways are desperately needed. NEDDylation is a key cellular process by which NEDD8 proteins are conjugated to substrate proteins in order to modulate their function. NEDDylation is closely tied to appropriate protein degradation, particularly proteins involved in cell cycle regulation, DNA damage repair, and cellular stress response. Components of the NEDDylation pathway are frequently overexpressed or hyperactivated in many cancer types including head and neck cancer, which contribute to disease progression and drug resistance. Therefore, targeting NEDDylation could have a major impact for malignancies with alterations in the pathway, and this has already been demonstrated in preclinical studies and clinical trials. Here, we will survey the mechanisms by which aberrant NEDDylation contributes to disease pathogenesis and discuss the potential clinical implications of inhibiting NEDDylation as a novel approach for the treatment of head and neck cancer. Full article
(This article belongs to the Special Issue Targeting Mechanisms of Protein Degradation for Cancer Therapy)
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19 pages, 1093 KiB  
Review
Mitochondrial ATP-Dependent Proteases—Biological Function and Potential Anti-Cancer Targets
by Yue Feng, Kazem Nouri and Aaron D. Schimmer
Cancers 2021, 13(9), 2020; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092020 - 22 Apr 2021
Cited by 11 | Viewed by 4091
Abstract
Cells must eliminate excess or damaged proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the ubiquitin-proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria proteases, including four core ATP-dependent proteases, m-AAA, i-AAA, [...] Read more.
Cells must eliminate excess or damaged proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the ubiquitin-proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria proteases, including four core ATP-dependent proteases, m-AAA, i-AAA, LonP, and ClpXP, located in the mitochondrial membrane and matrix. This review will discuss the function of mitochondrial proteases, with a focus on ClpXP as a novel therapeutic target for the treatment of malignancy. ClpXP maintains the integrity of the mitochondrial respiratory chain and regulates metabolism by degrading damaged and misfolded mitochondrial proteins. Inhibiting ClpXP genetically or chemically impairs oxidative phosphorylation and is toxic to malignant cells with high ClpXP expression. Likewise, hyperactivating the protease leads to increased degradation of ClpXP substrates and kills cancer cells. Thus, targeting ClpXP through inhibition or hyperactivation may be novel approaches for patients with malignancy. Full article
(This article belongs to the Special Issue Targeting Mechanisms of Protein Degradation for Cancer Therapy)
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Other

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12 pages, 1089 KiB  
Perspective
Presumed Roles of APRO Family Proteins in Cancer Invasiveness
by Yuka Ikeda, Kurumi Taniguchi, Haruka Sawamura, Sayuri Yoshikawa, Ai Tsuji and Satoru Matsuda
Cancers 2022, 14(19), 4931; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194931 - 08 Oct 2022
Cited by 4 | Viewed by 2100
Abstract
The APRO family members may be involved in the regulation of cell growth, migration, and/or invasion. Although an APRO protein could suppress the invasiveness of several cancer cells, it has been reported that overexpression of the same APRO protein could also promote the [...] Read more.
The APRO family members may be involved in the regulation of cell growth, migration, and/or invasion. Although an APRO protein could suppress the invasiveness of several cancer cells, it has been reported that overexpression of the same APRO protein could also promote the invasiveness and/or metastasis of the same cancer cells. In general, the invasiveness of cancer cells might be associated with the function of matrix metalloproteinases (MMPs) as well as with the function of certain exosomes. However, it has been shown that exosomes involving particular APRO proteins, MMPs, and/or microRNA could contribute to the regulation of invasiveness. Here, we discuss contradictory reports on invasiveness in relation to APRO family proteins on the basis of understanding the function of MMPs and/or various exosomes. A better understanding of those mechanisms could be of use to bring about innovative strategies for cancer treatment. Full article
(This article belongs to the Special Issue Targeting Mechanisms of Protein Degradation for Cancer Therapy)
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