Contribution of upregulated aminoacyl‐tRNA biosynthesis to metabolic dysregulation in gastric cancer

Journal of Gastroenterology and Hepatology, Journal Year: 2021, Volume and Issue: 36(11), P. 3113 - 3126

Published: June 23, 2021

Metabolic reprogramming is characterized by dysregulated levels of metabolites and metabolic enzymes. Integrated metabolomic transcriptomic data analysis can help to elucidate changes in the enzymes, screen core pathways, develop novel therapeutic strategies for cancer.Here, metabolome gastric cancer tissues was determined using liquid chromatography-mass spectrometry. The transcriptome from Cancer Genome Atlas dataset were integrated with spectrometry identify common cancer-specific pathways. Additionally, protein expression clinical significance key enzymes examined a tissue array.Metabolomic 16 revealed that among 15 aminoacyl-tRNA biosynthesis pathway markedly upregulated relative adjacent noncancerous tissues, which consistent results analysis. Bioinformatic regulators pathway, threonyl-tRNA synthetase (TARS) phenylalanyl-tRNA (FARSB) correlated tumor grade poor survival, respectively. array indicated TARS FARSB prognosis metastasis.This study demonstrated both play roles progression cancer. strategy proposed involves targeting pathway.

Language: Английский

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Long noncoding RNA HAGLR sponges miR‐338‐3p to promote 5‐Fu resistance in gastric cancer through targeting the LDHA‐glycolysis pathway

Cell Biology International, Journal Year: 2021, Volume and Issue: 46(2), P. 173 - 184

Published: Oct. 20, 2021

Gastric cancer (GC) is one of the most common human malignancies due to its invasiveness and metastasis. 5-Fu a widely applied chemotherapeutic agent against GC. Although therapy has achieved improvements in GC treatment, large fraction patients developed drug resistance which significantly limited clinical applications. Recent studies revealed pivotal roles long noncoding RNAs (lncRNAs) tumorigenesis progressions various tumors, including However, biological molecular mechanisms lncRNA HAGLR remain unclear. Here, we report was upregulated both tissues cell lines. In addition, associated with poorly survival rate patients. Blocking inhibited cells proliferation sensitized 5-Fu. Bioinformatical analysis luciferase assay demonstrated that sponged microRNA (miR)-338-3p, functions as tumor suppressor downregulate expressions. Moreover, from established resistant line (HGC27 R), detected elevated HAGLR, downregulated miR-338-3p, glucose metabolism compared parental HGC27 cells. We identified lactate dehydrogenase-A (LDHA), key enzyme, direct target miR-338-3p Rescue experiments restoration HAGLR-overexpressing R successfully overrode HAGLR-promoted through targeting LDHA. Taken together, this study essential for HAGLR-mediated GC, contributing development new RNA-based therapeutic strategies chemoresistant

Language: Английский

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Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

Cancers, Journal Year: 2021, Volume and Issue: 13(5), P. 1011 - 1011

Published: Feb. 28, 2021

Background: Despite substantial progress made in the last decades colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, promising strategy target tumor angiogenesis metabolically together with a sensitization of CRC chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation newly developed compounds such as KAN0438757 their effects on cells crucial steps preceding vivo preclinical studies, which turn may consolidate therapeutic targets. Materials Methods: The efficiency block expression translation human was evaluated immunoblotting real-time PCR. Functional vitro assays assessed cell viability, proliferation, survival, adhesion, migration invasion. Additionally, we matched patient-derived normal organoids its systemic toxicity C57BL6/N mice. Results: High is correlated worse survival patients. reduces protein without affecting transcriptional regulation. concentration-dependent anti-proliferative effect observed. invasion capacity were significantly reduced, independent effect. When treating colonic an impressive growth apparent, surprisingly sparing organoids. No high-grade observed vivo. Conclusion: inhibitor reduced migration, Moreover, showed significant growth, being overly toxic colon healthy Our findings strongly encourage further translational studies evaluate therapy.

Language: Английский

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SP and KLF Transcription Factors in Cancer Metabolism

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 9956 - 9956

Published: Sept. 1, 2022

Tumor development and progression depend on reprogramming of signaling pathways that regulate cell metabolism. Alterations to various metabolic such as glycolysis, oxidative phosphorylation, lipid metabolism, hexosamine biosynthesis pathway are crucial sustain increased redox, bioenergetic, demands a tumor cell. Transcription factors (oncogenes suppressors) play roles in modulating these alterations, their functions tethered major under homeostatic conditions disease initiation advancement. Specificity proteins (SPs) Krüppel-like (KLFs) closely related transcription characterized by three highly conserved zinc fingers domains interact with DNA. Studies have demonstrated SP KLF expressed tissues diverse processes proliferation, differentiation, apoptosis, inflammation, tumorigenesis. This review highlights the role metabolism cancers impact A better understanding underlying mechanisms governing changes during tumorigenesis could provide new therapeutic opportunities for cancer treatment.

Language: Английский

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Cancer metabolism control by natural products: Pyruvate kinase M2 targeting therapeutics

Phytotherapy Research, Journal Year: 2022, Volume and Issue: 36(8), P. 3181 - 3201

Published: July 6, 2022

Abstract Glycolysis is the primary source of energy for cancer growth and metastasis. The shift in metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis called Warburg effect. Cancer progression due often associated with activation oncogenes or loss tumor suppressors. Therefore, inhibition one effective strategies control. Pyruvate kinase M2 (PKM2) a key glycolytic enzyme overexpressed breast, prostate, lung, colorectal, liver cancers. Here, we discuss published studies regarding PKM2 inhibitors natural products that are promising drug candidates therapy. We have highlighted potential various types. Moreover, encourage researchers evaluate combinational effects between synthetic inhibitors. Also, further high‐quality needed firmly establish clinical efficacy products.

Language: Английский

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Glycolysis and chemoresistance in acute myeloid leukemia

Heliyon, Journal Year: 2024, Volume and Issue: 10(15), P. e35721 - e35721

Published: Aug. 1, 2024

While traditional high-dose chemotherapy can effectively prolong the overall survival of acute myeloid leukemia (AML) patients and contribute to better prognostic outcomes, advent chemoresistance is a persistent challenge effective AML management in clinic. The therapeutic resistance thought emerge owing heterogeneous adaptable nature tumor cells when exposed exogenous stimuli. Recent studies have focused on exploring metabolic changes that may afford novel opportunities treat AML, with particular focus glycolytic metabolism. Warburg effect, hallmark cancer, refers metabolism glucose through glycolysis under normoxic conditions, which contributes development chemoresistance. Despite key significance this process context malignant transformation, underlying molecular mechanisms linking remain incompletely understood. This review offers an overview current status research relationship between chemotherapy, contributions transporters, enzymes, signaling pathways, non-coding RNAs, microenvironment relationship. Together, article will provide foundation for selection targets formulation new approaches treating AML.

Language: Английский

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Comprehensive Multi-Omics Analysis Reveals Aberrant Metabolism of Epstein–Barr-Virus-Associated Gastric Carcinoma

Cells, Journal Year: 2019, Volume and Issue: 8(10), P. 1220 - 1220

Published: Oct. 8, 2019

The metabolic landscape of Epstein–Barr-virus-associated gastric cancer (EBVaGC) remains to be elucidated. In this study, we used transcriptomics, metabolomics, and lipidomics comprehensively investigate aberrant metabolism in EBVaGC. Specifically, conducted gene expression analyses using microarray-based data from adenocarcinoma epithelial cell lines tissue samples patients with clinically advanced carcinoma. We also complementary metabolomics various mass spectrometry platforms. found a significant downregulation genes related pathways, especially the amino acids, lipids, carbohydrates. effect dysregulated was confirmed survival analysis 3951 patients. 57 upregulated metabolites 31 that were downregulated EBVaGC compared EBV-negative cancer. Sixty-nine mainly ether-linked phospholipids triacylglycerols, downregulated, whereas 45 phospholipids, upregulated. total, 15 metabolisms polar lipid-associated pathways involved alteration by EBV work, have described at multi-omics level. These findings could help elucidate mechanism oncogenesis.

Language: Английский

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Dapagliflozin Inhibits Cell Adhesion to Collagen I and IV and Increases Ectodomain Proteolytic Cleavage of DDR1 by Increasing ADAM10 Activity

Molecules, Journal Year: 2020, Volume and Issue: 25(3), P. 495 - 495

Published: Jan. 23, 2020

Dapagliflozin, empagliflozin, tofogliflozin, selective inhibitors of sodium-glucose cotransporter 2 (SGLT2), is used clinically to reduce circulation glucose levels in patients with type diabetes mellitus by blocking the reabsorption kidneys. Dapagliflozin metabolized and inactivated UGT1A9. Empagliflozin UGT1A9 other related isoforms UGT2B7, UGT1A3, UGT1A8. Tofogliflozin five different enzymes CYP2C18, CYP3A4, CYP3A5, CYP4A11, CYP4F3. treatment HCT116 cells, which express SGLT2 but not UGT1A9, results loss cell adhesion, whereas HepG2 both are resistant adhesion-related effects dapagliflozin. PANC-1 H1792 do either or also adhesion On hand, empagliflozin tofogliflozin HCT116, HepG2, PANC-1, cells as observed dapagliflozin treated cells. Knockdown shRNA increased sensitivity, overexpression protected against dapagliflozin-dependent loos adhesion. had no effect on cellular interactions fibronectin, vitronectin, laminin, it induced a interaction collagen I IV. In parallel, reduced protein full-length discoidin domain receptor (DDR1), concomitant appearance DDR1 cleavage products ectodomain shedding DDR1. line these observations, unmetabolized ADAM10 activity. significantly Y792 tyrosine phosphorylation leading decrement function detachment cancer Concomitant lines results, we experienced that CEA colon cancer, addition chemotherapy was decreased (case 1). alone after radiation therapy started rise cessation 2). CA19-9 two pancreatic combination 3 4 respectively). PIVKAII liver mellitus, CYFRA squamous lung 5 6 Taken together, data suggest potential role for anticancer SGLT2,

Language: Английский

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Identification and validation of a novel glycolysis-related gene signature for predicting the prognosis in ovarian cancer

Cancer Cell International, Journal Year: 2021, Volume and Issue: 21(1)

Published: July 6, 2021

Abstract Background Ovarian cancer (OC) is the most lethal gynaecological tumor. Changes in glycolysis have been proven to play an important role OC progression. We aimed identify a novel glycolysis-related gene signature better predict prognosis of patients with OC. Methods mRNA and clinical data were obtained from The Cancer Genome Atlas (TCGA), International Consortium (ICGC) Genotype Tissue Expression (GTEx) database. “limma” R package was used differentially expressed genes (DEGs). Then, multivariate Cox proportional regression model survival analysis develop signature. Furthermore, TCGA training set divided into two internal test sets for validation, while ICGC dataset as external set. A nomogram constructed set, relative proportions 22 types tumor-infiltrating immune cells evaluated using “CIBERSORT” package. enriched Kyoto Encyclopedia Genes Genomes (KEGG) pathways determined by single-sample enrichment (ssGSEA) “GSVA” Finally, expression function unreported ISG20 SEH1L explored immunohistochemistry, western blotting, qRT-PCR, proliferation, migration, invasion xenograft tumor assays. Results five-gene comprising ANGPTL4, PYGB, ISG20, IRS2 constructed. This could independent factors. incorporating three features constructed, calibration plot suggested that accurately rate. According ssGSEA, associated KEGG related axon guidance, mTOR signalling, tight junctions, etc. differed significantly between high-risk group low-risk group. levels lower tissues than normal tissues. Overexpression or suppressed migration Caov3 vitro growth tumors vivo. Conclusion Five identified incorporated risk can effectively assess guide treatment patients.

Language: Английский

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Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism

Stem Cell Research & Therapy, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 23, 2025

Language: Английский

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