Functional and pathologic association of aminoacyl-tRNA synthetases with cancer

Sung, Yulseung; Yoon, Ina; Han, Jung Min; Kim, Sung Hoon

doi:10.1038/s12276-022-00765-5

Cited by 25 publications

(35 citation statements)

References 104 publications

(122 reference statements)

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“…Despite their similarity across organisms, the sequence and topological differences between pathogenic microbial AARSs and human AARSs make it possible to design drugs that selectively inhibit pathogen AARSs 3 . AARSs suppression can be exploited for cancer chemotherapy since over-proliferating cancer cells are more sensitive to AARSs suppression than normal cells 4 . For these reasons, AARS are underexploited therapeutic targets 5 .…”

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confidence: 99%

Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion

et al. 2023

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Aminoacyl-tRNA synthetases (AARSs), a family of essential protein synthesis enzymes, are attractive targets for drug development. Although several different types of AARS inhibitors have been identified, AARS covalent inhibitors have not been reported. Here we present five unusual crystal structures showing that threonyl-tRNA synthetase (ThrRS) is covalently inhibited by a natural product, obafluorin (OB). The residue forming a covalent bond with OB is a tyrosine in ThrRS active center, which is not commonly modified by covalent inhibitors. The two hydroxyl groups on the o-diphenol moiety of OB form two coordination bonds with the conserved zinc ion in the active center of ThrRS. Therefore, the β-lactone structure of OB can undergo ester exchange reaction with the phenolic group of the adjacent tyrosine to form a covalent bond between the compound and the enzyme, and allow its nitrobenzene structure to occupy the binding site of tRNA. In addition, when this tyrosine was replaced by a lysine or even a weakly nucleophilic arginine, similar bonds could also be formed. Our report of the mechanism of a class of AARS covalent inhibitor targeting multiple amino acid residues could facilitate approaches to drug discovery for cancer and infectious diseases.

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confidence: 99%

Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion

et al. 2023

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“…Notably, nucleotide metabolism and aminoacyl-tRNA biosynthesis pathways stood out as particularly affected with many of the main genes involved in the two processes being downregulated. Aminoacyl-tRNA biosynthesis is directly involved in the progression of gastric cancer, and its targeting has been proposed as a viable treatment strategy 29,39 . Similarly, sustained and aberrant nucleotide metabolism is a critical component in cancer development as it constitutes a cancer dependency independently of cancer type, tissue of origin, or driving molecular alteration 40 .…”

Section: Discussionmentioning

confidence: 99%

Deciphering molecular mechanisms of synergistic growth reduction in kinase inhibitor combinations

Tsirvouli,

Martinez del Val,

Thommesen

et al. 2024

Preprint

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In cancer treatment, the persistent challenge of unresponsiveness of certain patients to drugs or the development of resistance post-treatment remains a significant concern. Drug combinations that synergistically reduce tumor growth emerge as a promising avenue to address this issue. Here, we aimed to characterize the mechanism of action of two synergistic drug combinations that target PI3K together with MEK1 or with TAK1 and used time course measurements of phosphoproteomics and transcriptomics in response to single inhibitors and their combinations. Our analysis untangled those responses driven by single drugs and responses that were unique to the combinations. We observed a high overlap between single-drug responses and their combinations, suggesting that single-drug mechanisms dominate the mechanism of action of the combinations of the kinase inhibitors. Despite a high overlap, both drug combinations exhibited a synergistic modulation of several cell fate regulators found at the convergence points of the targeted pathways, including the key regulator of intrinsic apoptosis BCL2L11. Interestingly, the responses in both combinations were largely limited to the targeted pathways, namely PI3K/AKT and MAPKs, with very limited change of any other additional cell fate decision pathways. In addition, we observed a strong downregulation of nucleotide metabolism and tRNA biosynthesis uniquely in the combinations, which could be attributed to the reduced activity of mTOR and ATF4. Our approach provides insights into the molecular mechanisms affected by the PI3Ki-TAK1i and PI3Ki-MEKi combinations and can serve as a flexible framework for dissecting drug combination responses based on multi-omics measurements.

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Section: Introductionmentioning

confidence: 99%

“…Recently, the continued interest in aminoacyl‐tRNA synthases (ARSs) has delivered their pathological significance in carcinogenesis and clinical implications in therapy 7,8 . ARSs as a class of catalytic enzymes transport amino acid to cognate tRNAs for cell protein synthesis 7 . Research has demonstrated that ARSs severed as regulators, sensing diverse cellular conditions and influencing various cellular processes, thus establishing connections with tumorigenesis 7 .…”

Section: Introductionmentioning

confidence: 99%

AARS2 as a novel biomarker for prognosis and its molecular characterization in pan‐cancer

Liu,

Gao,

Liu

et al. 2023

Cancer Medicine

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IntroductionThe mitochondrial alanyl‐tRNA synthetase 2 (AARS2) as one of aminoacyl‐tRNA synthases (ARSs) performs amino acid transportation and involves protein synthesis. However, its role in cancer remains largely unexplored.MethodsIn this study, more than 10,000 samples were enrolled to explore genomic alterations, biological function, prognosis, and clinical treatment based on AARS2 across pan‐cancer. The molecular characterization of AARS2 was confirmed in hepatocellular carcinoma (HCC) using proteomics analysis, quantitative real‐time PCR, western blotting, immunohistochemical staining, and cell experiments.ResultsFor genomic landscape, the AARS2 was dramatically upregulated in multiple cancers, which might be mainly caused by copy number alteration rather than mutation and methylation. The abnormal expression of AARS2 was prominently associated with activity of cancer pathways and performed oncogenic roles in most cancers. Systematic experiments in vitro substantiated the elevated expression of AARS2, and the deficiency of it inhibited cell proliferation and cell migration in HCC. Meanwhile, our findings suggested that AARS2 could serve as a novel promising and stable biomarker for assessing prognosis and immunotherapy. Moreover, a variety of therapeutic drugs and targeted pathways were proposed for cancer treatment, which might enhance clinical efficacy.ConclusionThe AARS2 could serve as a new oncogenic gene that promotes cell proliferation and migration in HCC. The comprehensive investigations increased the understanding of AARS2 across human cancers and generated beginning insights of AARS2 in genomic landscape, molecular biological function, prognosis, and clinical treatment.

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Functional and pathologic association of aminoacyl-tRNA synthetases with cancer

Cited by 25 publications

References 104 publications

Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion

Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion

Deciphering molecular mechanisms of synergistic growth reduction in kinase inhibitor combinations

AARS2 as a novel biomarker for prognosis and its molecular characterization in pan‐cancer

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