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Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies.

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 studie

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… IAPs induce NFκB activity through nondegradative polyubiquitination of inhibitory factor RIP1. Targeting IAPs showed promising results in several hematologic malignancies, from acute and chronic leukemias, to lymphomas and multiple myeloma (for review see [ 123 ]). …

Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms.

The onset of proteolysis targeting chimeras (PROTACs) has reshaped the entire context of targeted cancer therapy by offering a novel approach for the selective degradation of disease-causing proteins, overcoming the limitations of traditional occupancy-driven inhibition. This heterobifunctional technology recruits endogenous E3 ubiquitin ligases to mark proteins of interest (POI) for proteosomal degradation via the ubiquitin-proteasome system (UPS). Unlike conventional inhibitors, PROTACs function catalytically and can target previously "undruggable proteins", such as transcription factors, sc

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… Upon formation of the ternary complex, the E3 ligase promotes polyubiquitination of the target protein, thereby tagging it for subsequent degradation by the 26S proteosome [ 14 ]. …

Exosomes for angiogenesis induction in ischemic disorders.

Ischaemic disorders are leading causes of morbidity and mortality worldwide. While the current therapeutic approaches have improved life expectancy and quality of life, they are unable to "cure" ischemic diseases and instate regeneration of damaged tissues. Exosomes are a class of extracellular vesicles with an average size of 100-150 nm, secreted by many cell types and considered a potent factor of cells for paracrine effects. Since exosomes contain multiple bioactive components such as growth factors, molecular intermediates of different intracellular pathways, microRNAs and nucleic acids, t

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… downregulation | IV | 38 | Improve osteogenesis Prevent osteoporosis progression Increased trabecular bone mass Improve bone blood flow BM‐MSC | LncRNA H19‐mediated miR‐106a inhibition and Ang‐1/Tie2‐NO activation | IV | 212 Limb ischemia | Hind limb ischemia | Cardiac‐MSC | miR‐7116‐5p‐mediated protein polyubiquitination …

HDAC6-an Emerging Target Against Chronic Myeloid Leukemia?

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the

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… When the proteasome is degraded, the polyubiquitinated misfolded proteins are transported to the microtubule-organizing center and are supported by HDAC6 via its ubiquitin binding domain, leading to the formation of aggresomes through deacetylation of cortactin. …

Oncolytic myxoma virus and engineering strategies for advanced cancer immunotherapy.

In cancer immunotherapy, oncolytic viruses (OVs) offer an alternative approach to kill malignant cells by inducing cancer-specific host immune system activation. Given the ongoing need for safe and effective viral vectors for immunotherapy, non-zoonotic animal viruses have attracted significant interest. Here, we review the oncolytic myxoma virus (MYXV) and emphasize its emerging role in cancer immunotherapy. We critically discuss recent advances in cancer therapy using MYXV, primarily focused on engineered viral modifications. Furthermore, we briefly review alternative delivery strategies for

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… . | predicted | 13 , 15 , 32 M143R | M143R is a homolog of the RING-containing ubiquitin ligase p28 of orthopoxviruses and mediates the formation of polyubiquitin conjugates. …

A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders.

Molecular glue degraders (MGDs) constitute a class of innovative therapeutic agents within the field of targeted protein degradation (TPD). In contrast to proteolysis-targeting chimeras (PROTACs), MGDs induce protein degradation by stabilizing the interaction between an E3 ubiquitin ligase and a target protein. They typically exhibit favorable drug-like characteristics, including lower molecular weight and enhanced bioavailability. Although their discovery was historically serendipitous, recent advances in high-throughput screening, bioinformatics, and artificial intelligence are enabling more

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… This interaction facilitates ubiquitination of EGFR, particularly via K63-linked polyubiquitination, which marks the receptor for degradation through the autophagy-lysosome pathway. 3.2.4. …

Skeletal muscle dysfunction induced by cancer immunotherapy: mechanistics insights and surgical implications.

Cancer immunotherapy has revolutionized cancer treatment, yet its effects extend far beyond tumor eradication. Accumulating evidence indicates that immunotherapy-associated skeletal muscle dysfunction represents a complex, cross-organ pathological process driven by dynamic crosstalk between the tumor microenvironment and peripheral tissues. Rather than an isolated adverse event, muscle injury emerges from integrated mechanisms including inflammatory cytokine spillover, aberrant immune cell infiltration, metabolic reprogramming, vascular dysfunction, and impaired regenerative signaling. Central

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… These ligases selectively target critical structural and regulatory proteins, including myosin heavy chain, titin, and myogenic regulatory factors, for K48−linked polyubiquitination and subsequent degradation by the 26S proteasome, directly causing myofibrillar disassembly and reduced muscle mass ( 87 …

HMMR in human cancers: regulatory mechanism and biological function.

Hyaluronan-mediated motility receptor (HMMR), also referred to as RHAMM or CD168, has gained recognition as a multifunctional protein that mediates the transmission of extracellular matrix-derived hyaluronan (HA) signals to intracellular pathways regulating tumor growth, migration, and mitosis. Overexpression of HMMR is observed in various cancers, including head and neck squamous cell carcinoma, breast cancer, lung cancer, and prostate cancer, as well as several hematologic malignancies. This elevated expression correlates with poor prognosis, rendering it a valuable marker for survival predi

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… HMMR is targeted for degradation by the anaphase-promoting complex/cyclosome (APC/C) through recognition of multiple conserved degron motifs (D-box, KEN-box, TEK-box) in its C-terminal region, resulting in K11-linked polyubiquitination and subsequent proteasomal degradation [ 70 ]. …

The JAK/STAT signaling pathway: from bench to clinic.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pat

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… family negatively regulates the JAK/STAT pathway in three ways: (1) binding to a tyrosine kinase receptor to block the recruitment of STAT; (2) binding directly to JAK to inhibit its kinase activity; (3) forming an elongin B/C-cullin5 complex that degrades JAK or STAT bound to the SOCS protein through polyubiquitination … kinase activity through KIR. 164 (3) The SOCS proteins interact with the elongation protein B/C complex through its C-terminal SOCS box and simultaneously binds to the cullin5 scaffold protein to form an elongation protein-cullin-SOCS3 E3 ubiquitin-linked enzyme complex. 165 This complex undergoes polyubiquitination …

Marizomib in the therapy of brain tumors-how far did we go and where do we stand?

Out of several types of tumors of the central nervous system (CNS), glioblastoma (GBM) represents one of the most frequent and malignant forms of brain neoplasms. To date, GBM holds very limited therapeutic options leaving patients with poor prognosis of survival. As such, novel treatment approaches are constantly quested. One of these strategies is based on the utilization of proteasome inhibitors (PIs). However, although several PIs have been approved as therapy for patients with hematological malignancies, these treatment benefits cannot not be easily extrapolated to brain tumors. This is m

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… Protein polyubiquitination occurs in three stages: (I) activation of ubiquitin and its transfer to the E1 enzyme; (II) transfer of ubiquitin to the E2 conjugating enzyme; (III) transfer of ubiquitin by the E3 enzyme (ubiquitin ligase) to the protein [ 15 ]. …

NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression.

Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer.

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… As a sensor of heme, BACH1 binds heme and it induces not only its nuclear export but also its polyubiquitination and degradation ( Zenke-Kawasaki et al., 2007 ), thereby losing its activity as a repressor. …

miRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy.

Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recent

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… | TUBB3 | Interaction with TUBB3 to prevent its ubiquitination, macrophage M2 polarization, metastasis spreading, and proliferation of colon cancer cells | Colorectal cancer metastasis | [ 129 ] | lncRNA LINK-A | PtdIns (3,4,5) P3, inhibitory GCPRs, E3 ubiquitin ligase TRIM71 | Enhancement of K48–polyubiquitination-mediated …

Modulation of Angiogenic Processes by the Human Gammaherpesviruses, Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus.

Angiogenesis is the biological process by which new blood vessels are formed from pre-existing vessels. It is considered one of the classic hallmarks of cancer, as pathological angiogenesis provides oxygen and essential nutrients to growing tumors. Two of the seven known human oncoviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), belong to the Gammaherpesvirinae subfamily. Both viruses are associated with several malignancies including lymphomas, nasopharyngeal carcinomas, and Kaposi's sarcoma. The viral genomes code for a plethora of viral factors, includin

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… EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS Pathog. 9:e1003510. 10.1371/journal.ppat.1003510 Dwyer J., Le Guelte A., Galan Moya E. …

Семья гистона деацетилазы в здравии и болезни.

Классические деацетилазы, включая классы I, II и IV, в зависимости от цинка, повсеместно присутствуют у млекопитающих и играют жизненно важную роль в многочисленных биологических процессах. На сегодняшний день eleven Были выявлены члены < < хисттон деацетилаза > > , а именно < < хиттон деацетилаза > > . 1 через гистонную деацетилазу 11. Растущий объем данных подчеркивает важнейшую роль этих гистоновых деацетилазов как в физиологических, так и патологических условиях. В частности, эти гистонные деацетилазы участвуют в различных клеточных процессах, включая воспаление, ме

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… its ubiquitin-binding zinc finger domain. 133 HDAC6 also interacts with p62 134 , a scaffolding protein that mediates the delivery of protein aggregates and damaged organelles to autophagosomes. 135 For instance, Kawaguchi et al. 136 discovered that HDAC6 is a core component of aggresomes, binding polyubiquitinated …

Molecular targeted therapy for anticancer treatment.

Since the initial clinical approval in the late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served as a fundamental backbone in precision medicine for cancer treatment. These approaches are now used clinically as first-line therapy for various types of human cancers. Compared to conventional chemotherapy, targeted therapeutic agents have efficient anticancer effects with fewer side effects. However, the emergence of drug resistanc

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… interactions with other proteins to disrupt or maintain autoinhibitory conformation, and posttranslational modifications such as trans- or Src-mediated tyrosine phosphorylation (e.g., activation of ABL1 by phosphorylation at Y245 and Y412), serine/threonine phosphorylation, acetylation, myristoylation, and polyubiquitination …

Autophagy in tumor immune escape and immunotherapy.

The immunotherapy targeting tumor immune escape mechanisms has become a critical strategy in anticancer treatment; however, the challenge of immune resistance remains significant. Autophagy, a cellular response to various stressors, involves the degradation of damaged proteins and organelles via lysosomal pathways, maintaining cellular homeostasis. This process not only supports tumor cell survival but also profoundly impacts the efficacy of cancer immunotherapies. The modulation of autophagy in tumor cells or immune cells exerts dual effects on tumor immune escape and immunotherapy. However,

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… In this process, p62, which acts as a bridge linking LC3 and polyubiquitinated proteins, is selectively wrapped into the autophagosome, after which it is degraded by proteohydrolases in the autophagic lysosome [ 21 , 28 ]. …

Identification and transformation of novel targets for immunotherapy in multiple myeloma.

AbstractMultiple myeloma (MM), a clonal plasma cell malignancy characterized by high chromosomal instability and inevitable relapse. Increased understanding of immune dysregulation and suppression during MM progression has led to the development of various immunotherapies over the past two decades. Immunotherapeutic strategies, including immunomodulatory imide drugs, monoclonal antibodies, immune checkpoint inhibitors, antibody-drug conjugates, chimeric antigen receptor T cells, and bispecific T cell engagers, have been evaluated in numerous clinical trials and demonstrated significant clinica

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… induction, and cell growth inhibition. [ 49 ] The mechanism of these drugs remained unclear until the 2010s, when cereblon (CRBN) was identified as a key target of thalidomide. [ 50 , 51 ] IMiDs act as a molecular glue: These drugs bind CRBN and link neosubstrates to the CRL4CRBN complex, leading to polyubiquitination …

Potential Therapeutic Targets of Resveratrol, a Plant Polyphenol, and Its Role in the Therapy of Various Types of Cancer.

Cancer is among the most prominent causes of mortality worldwide. Different cancer therapy modes employed, including chemotherapy and radiotherapy, have been reported to be significant in cancer management, but the side effects associated with these treatment strategies are still a health problem. Therefore, alternative anticancer drugs based on medicinal plants or their active compounds have been generating attention because of their less serious side effects. Medicinal plants are an excellent source of phytochemicals that have been recognized to have health-prompting effects through modulati

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention.

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death pr

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… Namely, cIAP ligands function as E3 ubiquitin ligases that target RIP1 for polyubiquitination and have shown success in the design of PROTACs [ 247 , 255 ]. …

FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review.

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug

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… The polyubiquitin (poly-Ub) chain, the most abundant Lys48-linked poly-Ub (Ub Lys48 ) chain, is an intracellular signal to shuttle the target proteins to the proteasome, where they are proteolytically broken down [ 139 ]. …