Ribosome biogenesis in disease: new players and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 9, 2023

Abstract The ribosome is a multi-unit complex that translates mRNA into protein. Ribosome biogenesis the process generates ribosomes and plays an essential role in cell proliferation, differentiation, apoptosis, development, transformation. mTORC1, Myc, noncoding RNA signaling pathways are primary mediators work jointly with polymerases proteins to control protein synthesis. Activation of mTORC1 required for normal fetal growth development tissue regeneration after birth. Myc implicated cancer by enhancing Pol II activity, leading uncontrolled growth. deregulation RNAs such as microRNAs, long RNAs, circular involved developing blood, neurodegenerative diseases, atherosclerosis. We review similarities differences between eukaryotic bacterial molecular mechanism ribosome-targeting antibiotics resistance. also most recent findings dysfunction COVID-19 other conditions discuss consequences frameshifting, ribosome-stalling, ribosome-collision. summarize various diseases. Furthermore, we current clinical trials, prospective vaccines COVID-19, therapies targeting cancer, cardiovascular disease, aging, disease.

Language: Английский

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METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer

Redox Biology, Journal Year: 2024, Volume and Issue: 71, P. 103087 - 103087

Published: Feb. 13, 2024

Ferroptosis, an iron-dependent lipid peroxidation-induced form of regulated cell death, shows great promise as a cancer therapy strategy. Despite the critical role mitochondria in ferroptosis regulation, underlying mechanisms remain elusive. This study reveals that mitochondrial protein METTL17 governs function colorectal (CRC) cells through epigenetic modulation. Bioinformatic analysis establishes expression positively correlates with resistance and is up-regulated CRC. Depletion sensitizes CRC to ferroptosis, impairs proliferation, migration, invasion, xenograft tumor growth, AOM/DSS-induced tumorigenesis. Furthermore, suppression disrupts function, energy metabolism, enhances intracellular peroxidation ROS levels during ferroptotic stress. Mechanistically, inhibition significantly reduces RNA methylation, including m4C, m5C, m3C, m7G, m6A, leading impaired translation protein-coding genes. Additionally, interacting proteins associated are essential for gene expression, their knockdown inhibits proliferation. Notably, combined targeting therapeutic approach effectively suppresses growth vivo. uncovers METTL17-mediated defense mechanism survival mitochondria, highlighting potential target

Language: Английский

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Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells

Redox Biology, Journal Year: 2021, Volume and Issue: 47, P. 102144 - 102144

Published: Sept. 21, 2021

Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein 5-FU, and elevated TS lowers CRC cells. Here, we tested efficacy several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor P53 HT29 mutant P53. Among them, found that apigenin enhanced inhibitory effect on cell viability. In addition, inhibited upregulation induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis cycle disruption. Furthermore, increased reactive oxygen species production, intracellular intramitochondrial Ca2+ concentrations, mitochondrial membrane potential upon cotreatment with Knockdown forkhead box M, transcription factor modulating sensitivity, potentiation in Moreover, suppressed expression viability 5-FU-resistant Therefore, may improve suppressing TS, but induction mainly dependent functional

Language: Английский

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Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

Cancers, Journal Year: 2022, Volume and Issue: 14(6), P. 1462 - 1462

Published: March 12, 2022

Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One well-known mechanisms change mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or selective autophagy, for cell quality control because it can efficiently break down, remove, and recycle defective damaged mitochondria. As use mitophagy to rapidly sweep away mitochondria order mediate their own drug resistance, influences efficacy tumor well degree resistance. Yet despite importance little known about precise involved. a consequence, identifying potential therapeutic targets by analyzing signal that govern has become vital research goal. In this paper, we review recent advances research, mechanisms, implications our understanding

Language: Английский

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DDX5 and DDX17—multifaceted proteins in the regulation of tumorigenesis and tumor progression

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Aug. 3, 2022

DEAD-box (DDX)5 and DDX17, which belong to the RNA helicase family, are nuclear cytoplasmic shuttle proteins. These proteins expressed in most tissues cells participate regulation of normal physiological functions; their abnormal expression is closely related tumorigenesis tumor progression. DDX5/DDX17 almost all processes metabolism, such as alternative splicing mRNA, biogenesis microRNAs (miRNAs) ribosomes, degradation interaction with long noncoding RNAs (lncRNAs) coregulation transcriptional activity. Moreover, different posttranslational modifications, phosphorylation, acetylation, ubiquitination, sumoylation, endow functions Indeed, DDX5 DDX17 also interact multiple key tumor-promoting molecules progression signaling pathways. When or modification dysregulated, cellular network collapses, leading many pathological states, including development. This review mainly discusses molecular structure features biological effects on progression, well potential clinical application for treatment.

Language: Английский

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SIRT7: the seventh key to unlocking the mystery of aging

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 253 - 280

Published: Sept. 7, 2023

Aging is a chronic yet natural physiological decline of the body. Throughout life, humans are continuously exposed to variety exogenous and endogenous stresses, which engender various counteractive responses at cellular, tissue, organ, as well organismal levels. The compromised cellular tissue functions that occur because genetic factors or prolonged stress (or even response) may accelerate aging. Over last two decades, sirtuin (SIRT) family lysine deacylases has emerged key regulator longevity in organisms. SIRT7, most recently identified member SIRTs, maintains homeostasis provides protection against aging by functioning watchdog genomic integrity, dynamic sensor modulator stresses. SIRT7 disrupts metabolic homeostasis, accelerates aging, increases risk age-related pathologies including cardiovascular neurodegenerative diseases, pulmonary renal disorders, inflammatory cancer, etc. Here, we present seventh unlock mystery its specific manipulation holds great potential ensure healthiness longevity.

Language: Английский

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RNA-binding protein RPS7 promotes hepatocellular carcinoma progression via LOXL2-dependent activation of ITGB1/FAK/SRC signaling

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Feb. 8, 2024

Metastasis is one of the leading cause contributes to treatment failure and poor prognosis hepatocellular carcinoma (HCC) patients. The underlying mechanism HCC metastasis remains be determined. Although several RNA binding proteins (RBPs) have been found participate in tumorigenesis progression liver cancer, role RBPs patients with extrahepatic metastases poorly understood. By performing RNA-seq primary tissues (including those did not develop metastasis), we identified a set metastasis-associated candidates. Among which, ribosomal protein S7 (RPS7) was remarkably increased strongly related survival. Overexpression or CRISPR-Cas9-mediated knockout were applied investigate RPS7 on phenotypes cells. sequencing, RIP, RNA-pull down, dual luciferase reporter assay, nascent capture decay so on, reveal induced metastasis. Gain- loss- function analyses revealed that promoted cells adhesion, migration invasion capabilities, as well lung Mechanistically, uncovered lysyl oxidase-like 2 (LOXL2) critical downstream target RPS7. could stabilize LOXL2 mRNA by AUUUA motifs 3155-3375 region 3'UTR mRNA, thus expression via elevating abundance. Further research accelerate focal adhesion formation through maintaining stability ITGB1 activating ITGB1-mediated FAK/SRC signaling pathway, thereby contribute pro-metastasis effect Taken together, our data novel metastasis, also roles RPS7/LOXL2/ITGB1 axis shed new light exploration molecular drugs against HCC.

Language: Английский

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AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 30, 2024

Due to low success rates and long cycles of traditional drug development, the clinical tendency is apply omics techniques reveal patient-level disease characteristics individualized responses treatment. However, heterogeneous form data uneven distribution targets make discovery precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as paradigm uses mining large TNBC cohort databases establish biofactor-regulated neural network rapidly screening optimizing compound pairs. Subsequently, biomimetic nanococrystals are prepared using preferred combination mitoxantrone gambogic acid rational delivery. The unique mechanism obtained regulating genes through ribosomal stress triggering cascade immune effects revealed in models. In this work, target omics-based intelligent framework explores an innovative development paradigm, which repurposes existing drugs enables precise treatment refractory diseases.

Language: Английский

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Anaplasma phagocytophilum AFAP targets the host nucleolus and inhibits induced apoptosis

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 7, 2025

Anaplasma phagocytophilum, the etiologic agent of human granulocytic anaplasmosis (HGA), is an obligate intracellular Gram-negative bacterium. During infection, A. phagocytophilum transfers its type IV secretion system (T4SS) effector proteins into host cells to manipulate cellular processes. AFAP (an actin filament-associated protein) was identified as a T4SS protein and found interact with nucleolin, described in previous study. In this study, proteomic analysis performed extensively identify AFAP-interacting analyze potential role modulating A total 586 were interacting by data-independent acquisition mass spectrometry annotated 501 Gene Ontology (GO) terms, significantly over-represented ones related ribosomes, nucleolus, DNA binding, rRNA metabolic process. Given nucleolus stress response, targeting identification dozens that GO term (GO:0072331, signal transduction p53 class mediator), apoptosis determined. capable inhibiting induced apoptosis. Thus, determination anti-apoptotic activity may help elucidate HGA pathogenesis.

Language: Английский

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Mitochondrial Ribosomal Proteins and Cancer

Medicina, Journal Year: 2025, Volume and Issue: 61(1), P. 96 - 96

Published: Jan. 9, 2025

Mitochondria play key roles in maintaining cell life and function, their dysfunction can lead to damage. Mitochondrial ribosomal proteins (MRPs) are encoded by nuclear genes assembled within the mitochondria. MRPs pivotal components of mitochondrial ribosomes, which responsible for translating 13 DNA-encoded essential respiratory chain. Recent studies have underscored importance cancer biology, revealing altered expression patterns various types potential as both prognostic biomarkers therapeutic targets. Herein, we review current knowledge regarding multiple functions structure ribosome apoptosis, implications susceptibility progression, innovative strategies being developed target mitoribosome biogenesis therapy. This comprehensive overview aims provide insights into role biology highlight promising future precision oncology.

Language: Английский

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