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Nature Reviews. Clinical Oncology Aug 2023N-Methyladenosine (mA), the most prevalent internal modification in eukaryotic mRNA, has been extensively and increasingly studied over the past decade. Dysregulation of... (Review)
Review
N-Methyladenosine (mA), the most prevalent internal modification in eukaryotic mRNA, has been extensively and increasingly studied over the past decade. Dysregulation of RNA mA modification and its associated machinery, including writers, erasers and readers, is frequently observed in various cancer types, and the dysregulation profiles might serve as diagnostic, prognostic and/or predictive biomarkers. Dysregulated mA modifiers have been shown to function as oncoproteins or tumour suppressors with essential roles in cancer initiation, progression, metastasis, metabolism, therapy resistance and immune evasion as well as in cancer stem cell self-renewal and the tumour microenvironment, highlighting the therapeutic potential of targeting the dysregulated mA machinery for cancer treatment. In this Review, we discuss the mechanisms by which mA modifiers determine the fate of target RNAs and thereby influence protein expression, molecular pathways and cell phenotypes. We also describe the state-of-the-art methodologies for mapping global mA epitranscriptomes in cancer. We further summarize discoveries regarding the dysregulation of mA modifiers and modifications in cancer, their pathological roles, and the underlying molecular mechanisms. Finally, we discuss mA-related prognostic and predictive molecular biomarkers in cancer as well as the development of small-molecule inhibitors targeting oncogenic mA modifiers and their activity in preclinical models.
Topics: Humans; RNA; Adenosine; Neoplasms; RNA, Messenger; Biomarkers; Tumor Microenvironment
PubMed: 37221357
DOI: 10.1038/s41571-023-00774-x -
Molecular Cancer Aug 2023Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose... (Review)
Review
Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cancer. The n6-methyladenosine (m6A) modification of RNA is widespread in eukaryotic cells. Dynamic and reversible m6A modifications are widely involved in the regulation of cancer stem cell renewal and differentiation, tumor therapy resistance, tumor microenvironment, tumor immune escape, and tumor metabolism. Lately, more and more evidences show that m6A modification can affect the glycolysis process of tumors in a variety of ways to regulate the biological behavior of tumors. In this review, we discussed the role of glycolysis in tumor genesis and development, and elaborated in detail the profound impact of m6A modification on different tumor by regulating glycolysis. We believe that m6A modified glycolysis has great significance and potential for tumor treatment.
Topics: Humans; Neoplasms; Epigenesis, Genetic; Glycolysis; Epigenomics; Adenosine; Tumor Microenvironment
PubMed: 37582735
DOI: 10.1186/s12943-023-01841-8 -
Frontiers in Immunology 2023Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and... (Review)
Review
Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and autoimmune diseases have high incidence rates, still threaten human health, and represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis of various diseases. As the most widely discussed m6A methyltransferase, the pathogenic role of METTL3 in inflammatory diseases has become a research hotspot, but there has been no comprehensive review of the topic. Here, we summarize the expression changes, modified target genes, and pathogenesis related to METTL3 in cardiovascular, metabolic, degenerative, immune, and infectious diseases, as well as tumors. In addition to epithelial cells, endothelial cells, and fibroblasts, METTL3 also regulates the function of inflammation-related immune cells, including macrophages, neutrophils, dendritic cells, Th17 cells, and NK cells. Regarding therapeutic applications, METTL3 serves as a target for the treatment of inflammatory diseases with natural plant drug components, such as emodin, cinnamaldehyde, total flavonoids of , and resveratrol. This review focuses on recent advances in the initiation, development, and therapeutic application of METTL3 in inflammatory diseases. Knowledge of the specific regulatory mechanisms involving METTL3 can help to deepen understanding of inflammatory diseases and lay the foundation for the development of precisely targeted drugs to address inflammatory processes.
Topics: Humans; Endothelial Cells; Methyltransferases; Adenosine; Atherosclerosis; Autoimmune Diseases; Cardiovascular Diseases
PubMed: 37671161
DOI: 10.3389/fimmu.2023.1221609 -
Science Immunology Jul 2023The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the... (Review)
Review
The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
Topics: Humans; Neoplasms; Adenosine; Adenosine Triphosphate; Adenosine Monophosphate; DNA Damage; Tumor Microenvironment
PubMed: 37418547
DOI: 10.1126/sciimmunol.abq3015 -
Cell Dec 2023Transfer RNA (tRNA) modifications are critical for protein synthesis. Queuosine (Q), a 7-deaza-guanosine derivative, is present in tRNA anticodons. In vertebrate tRNAs...
Transfer RNA (tRNA) modifications are critical for protein synthesis. Queuosine (Q), a 7-deaza-guanosine derivative, is present in tRNA anticodons. In vertebrate tRNAs for Tyr and Asp, Q is further glycosylated with galactose and mannose to generate galQ and manQ, respectively. However, biogenesis and physiological relevance of Q-glycosylation remain poorly understood. Here, we biochemically identified two RNA glycosylases, QTGAL and QTMAN, and successfully reconstituted Q-glycosylation of tRNAs using nucleotide diphosphate sugars. Ribosome profiling of knockout cells revealed that Q-glycosylation slowed down elongation at cognate codons, UAC and GAC (GAU), respectively. We also found that galactosylation of Q suppresses stop codon readthrough. Moreover, protein aggregates increased in cells lacking Q-glycosylation, indicating that Q-glycosylation contributes to proteostasis. Cryo-EM of human ribosome-tRNA complex revealed the molecular basis of codon recognition regulated by Q-glycosylations. Furthermore, zebrafish qtgal and qtman knockout lines displayed shortened body length, implying that Q-glycosylation is required for post-embryonic growth in vertebrates.
Topics: Animals; Humans; Rats; Anticodon; Cell Line; Codon; Glycosylation; Nucleoside Q; RNA, Transfer; Swine; Zebrafish; Nucleic Acid Conformation
PubMed: 37992713
DOI: 10.1016/j.cell.2023.10.026 -
Biomedicine & Pharmacotherapy =... Jul 2023Gastric cancer (GC) is a fatal illness, and its mortality rate is very high all over the world. At present, it is a serious health problem for any country. It is a... (Review)
Review
Gastric cancer (GC) is a fatal illness, and its mortality rate is very high all over the world. At present, it is a serious health problem for any country. It is a multifactorial disease due to the rising drug resistance and the increasing global cancer burden, the treatment of GC still faces many obstacles and problems. In recent years, research on GC is being carried out continuously, and we hope to address the new targets of GC treatment through this review. At the same time, we also hope to discover new ways to fight GC and create more gospel for clinical patients. First, we discuss the descriptive tumor microenvironment (TME), N6-methyladenosine (m6A), pyroptosis, autophagy, ferroptosis, and cuproptosis. Finally, we expounded on the new or potential targets of GC treatment.
Topics: Humans; Stomach Neoplasms; Ferroptosis; Pyroptosis; Tumor Microenvironment; Adenosine; Autophagy
PubMed: 37196545
DOI: 10.1016/j.biopha.2023.114883 -
ELife Dec 2023Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Topics: Leishmania donovani; Ligands; Phosphotransferases; Cyclic AMP-Dependent Protein Kinases; Purine Nucleosides; Trypanosoma brucei brucei
PubMed: 38126364
DOI: 10.7554/eLife.94720 -
Phytomedicine : International Journal... Dec 2023Current evidence indicates a rising global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), which is closely associated to conditions such as obesity,...
BACKGROUND
Current evidence indicates a rising global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD), which is closely associated to conditions such as obesity, dyslipidemia, insulin resistance, and metabolic syndrome. The relationship between the gut microbiome and metabolites in NAFLD is gaining attention understanding the pathogenesis and progression of dysregulated lipid metabolism and inflammation. The Xie Zhuo Tiao Zhi (XZTZ) decoction has been employed in clinical practice for alleviating hyperlipidemia and symptoms related to metabolic disorders. However, the pharmacological mechanisms underlying the effects of XZTZ remain to be elucidated.
PURPOSE
The objective of this study was to examine the pharmacological mechanisms underlying the hypolipidemic and anti-inflammatory effects of XZTZ decoction in a mouse model of NAFLD, as well as the effects of supplementing exogenous metabolites on PO induced cell damage and lipid accumulation in cultured hepatocytes.
METHODS
A high-fat diet (HFD) mouse model was established to examine the effects of XZTZ through oral gavage. The general condition of mice and the protective effect of XZTZ on liver injury were evaluated using histological and biochemical methods. Hematoxylin and eosin staining (H&E) staining and oil red O staining were performed to assess inflammatory and lipid accumulation detection, and cytokine levels were quantitatively analyzed. Additionally, the study included full-length 16S rRNA sequencing, liver transcriptome analysis, and non-targeted metabolomics analysis to investigate the relationship among intestinal microbiome, liver metabolic function, and XZTZ decoction.
RESULTS
XZTZ had a significant impact on the microbial community structure in NAFLD mice. Notably, the abundance of Ileibacterium valens, which was significantly enriched by XZTZ, exhibited a negative correlation with liver injury biomarkers such as, alanine transaminase (ALT) and aspartate transaminase (AST) activity. Moreover, treatment with XZTZ led to a significant enrichment of the purine metabolism pathway in liver tissue metabolites, with inosine, a purine metabolite, showing a significant positive correlation with the abundance of I. valens. XZTZ and inosine also significantly enhanced fatty acid β-oxidation, which led to a reduction in the expression of pro-inflammatory cytokines and the inhibition of liver pyroptosis. These effects contributed to the mitigation of liver injury and hepatocyte damage, both in vivo and vitro. Furthermore, the utilization of HPLC fingerprints and UPLC-Q-TOF-MS elucidated the principal constituents within the XZTZ decoction, including naringin, neohesperidin, atractylenolide III, 23-o-Acetylalisol B, pachymic acid, and ursolic acid which are likely responsible for its therapeutic efficacy. Further investigations are imperative to fully uncover and validate the pharmacodynamic mechanisms underlying these observations.
CONCLUSION
The administration of XZTZ decoction demonstrates a protective effect on the livers of NAFLD mice by inhibiting lipid accumulation and reducing hepatocyte inflammatory damage. This protective effect is mediated by the upregulation of I.valens abundance in the intestine, highlighting the importance of the gut-liver axis. Furthermore, the presesnce of inosine, adenosine, and their derivatives are important in promoting the protective effects of XZTZ. Furthermore, the in vitro approaching, we provide hitherto undocumented evidence indicating that the inosine significantly improves lipid accumulation, inflammatory damage, and pyroptosis in AML12 cells incubated with free fatty acids.
Topics: Animals; Mice; Non-alcoholic Fatty Liver Disease; Gastrointestinal Microbiome; Pyroptosis; RNA, Ribosomal, 16S; Liver; Lipid Metabolism; Diet, High-Fat; Fatty Acids, Nonesterified; Purines; Inosine; Mice, Inbred C57BL
PubMed: 37804819
DOI: 10.1016/j.phymed.2023.155111 -
Nature Cancer Jan 2024Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer...
Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.
Topics: Humans; Glycogen Synthase Kinase 3; S-Adenosylmethionine; Liver Neoplasms; Methionine; Methionine Adenosyltransferase
PubMed: 38168934
DOI: 10.1038/s43018-023-00671-3 -
Cancer Cell Feb 2024Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado...
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
Topics: Humans; T-Lymphocytes; Inosine
PubMed: 38278150
DOI: 10.1016/j.ccell.2024.01.002