Upregulation of Cystathionine-β-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

Phillips, Ches'Nique M.; Zatarain, John R.; Nicholls, Michael E. R.; Porter, Craig; Widen, Steve G.; Thanki, Ketan; Johnson, Paul; Jawad, Muhammad Umar; Moyer, Mary Pat; Randall, James W.; Hellmich, Judith L.; Maskey, Manjit; Qiu, Suimin; Wood, Thomas G.; Druzhyna, Nadiya; Szczesny, Bartosz; Módis, Katalin; Szabó, Csaba; Chao, Celia; Hellmich, Mark R.

doi:10.1158/0008-5472.can-16-3480

Cited by 109 publications

(95 citation statements)

References 41 publications

(46 reference statements)

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“…Compared with normal bone samples, a total of 346 DEGs were identified in the osteosarcoma cells, containing 43 up-regulated and 303 down-regulated genes. CBS (cystathionine-β-synthase cancer), the most regulated gene in this study, was found to be upregulated in many types of tumors, such as multiple myeloma [ 14 ], colorectal cancers [ 15 ], bladder cancer [ 16 ] and et al, and downregulation of CBS help inhibit carcinogenesis. However, to our knowledge, there was no report about CBS in osteosarcoma, so it might be a novel target for the diagnosis or treatment of osteosarcoma.…”

Section: Discussionmentioning

confidence: 80%

Identification of potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma

Pan

Chen

et al. 2018

Hereditas

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BackgroundThis study aimed to identify potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma by comprehensive bioinformatics analysis.MethodsData of gene expression profiles (GSE28424) and miRNA expression profiles (GSE28423) were downloaded from GEO database. The differentially expressed genes (DEGs) and miRNAs (DEMIs) were obtained by R Bioconductor packages. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein–protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. The relationships among the DEGs and module in PPI network were analyzed by plug-in NetworkAnalyzer and MCODE seperately. Through the TargetScan and comparing target genes with DEGs, the miRNA-mRNA regulation network was established.ResultsTotally 346 DEGs and 90 DEMIs were found to be differentially expressed. These DEGs were enriched in biological processes and KEGG pathway of inflammatory immune response. 25 genes in the PPI network were selected as hub genes. Top 10 hub genes were TYROBP, HLA-DRA, VWF, PPBP, SERPING1, HLA-DPA1, SERPINA1, KIF20A, FERMT3, HLA-E. PPI network of DEGs followed a pattern of power law network and met the characteristics of small-world network. MCODE analysis identified 4 clusters and the most significant cluster consisted of 11 nodes and 55 edges. SEPP1, CKS2, TCAP, BPI were identified as the seed genes in their own clusters, respectively. The miRNA-mRNA regulation network which was composed of 89 pairs was established. MiR-210 had the highest connectivity with 12 target genes. Among the predicted target of MiR-96, HLA-DPA1 and TYROBP were the hub genes.ConclusionOur study indicated possible differentially expressed genes and miRNA, and microRNA-mRNA negative regulatory networks in osteosarcoma by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of osteosarcoma.

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Section: Discussionmentioning

confidence: 80%

Identification of potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma

Pan

Chen

et al. 2018

Hereditas

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“…In particular in human colon cancer, the most significant upregulation in tumor tissue (compared to surrounding tissue) was noted in CBS, with a trend for increase for 3-MST [26]. Likewise, in many human colon cancer cell lines, CBS was found to be highly expressed, and genetic silencing or pharmacological inhibition of CBS exerted antitumor effects in vitro and in vivo [24][25][26][37][38][39][40][41] while forced expression of CBS into non-transformed human epithelial cells increased their growth in situ (but did not render them metastatic) [42]. In contrast, in the current, murine colon cancer cell line, CBS (mRNA or protein) was undetectable (and, accordingly, the CBS inhibitor AOAA was without significant biological effects), while 3-MST was highly expressed.…”

Section: Discussionmentioning

confidence: 96%

Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation, Migration, and Bioenergetics in Murine Colon Cancer Cells

et al. 2020

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3-mercaptopyruvate sulfurtransferase (3-MST) has emerged as one of the significant sources of biologically active sulfur species in various mammalian cells. The current study was designed to investigate the functional role of 3-MST's catalytic activity in the murine colon cancer cell line CT26. The novel pharmacological 3-MST inhibitor HMPSNE was used to assess cancer cell proliferation, migration and bioenergetics in vitro. Methods included measurements of cell viability (MTT and LDH assays), cell proliferation and in vitro wound healing (IncuCyte) and cellular bioenergetics (Seahorse extracellular flux analysis). 3-MST expression was detected by Western blotting; H 2 S production was measured by the fluorescent dye AzMC. The results show that CT26 cells express 3-MST protein and mRNA, as well as several enzymes involved in H 2 S degradation (TST, ETHE1). Pharmacological inhibition of 3-MST concentration-dependently suppressed H 2 S production and, at 100 and 300 µM, attenuated CT26 proliferation and migration. HMPSNE exerted a bell-shaped effect on several cellular bioenergetic parameters related to oxidative phosphorylation, while other bioenergetic parameters were either unaffected or inhibited at the highest concentration of the inhibitor tested (300 µM). In contrast to 3-MST, the expression of CBS (another H 2 S producing enzyme which has been previously implicated in the regulation of various biological parameters in other tumor cells) was not detectable in CT26 cells and pharmacological inhibition of CBS exerted no significant effects on CT26 proliferation or bioenergetics. In summary, 3-MST catalytic activity significantly contributes to the regulation of cellular proliferation, migration and bioenergetics in CT26 murine colon cancer cells. The current studies identify 3-MST as the principal source of biologically active H 2 S in this cell line.

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“…The Boyden chamber cell migration assay was used as previously described (Phillips et al, 2017;Szabo et al, 2013). Briefly, 10 5 EA.…”

Section: Boyden Chamber Cell Migration Assaymentioning

confidence: 99%

3‐Mercaptopyruvate sulfurtransferase supports endothelial cell angiogenesis and bioenergetics

Govar

Törő

Szaniszlo

et al. 2019

British J Pharmacology

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Background and Purpose During angiogenesis, quiescent endothelial cells (ECs) are activated by various stimuli to form new blood vessels from pre‐existing ones in physiological and pathological conditions. Many research groups have shown that hydrogen sulfide (H2S), the newest member of the gasotransmitter family, acts as a proangiogenic factor. To date, very little is known about the regulatory role of 3‐mercaptopyruvate sulfurtransferase (3‐MST), an important H2S‐producing enzyme in ECs. The aim of our study was to explore the potential role of 3‐MST in human EC bioenergetics, metabolism, and angiogenesis. Experimental Approach To assess in vitro angiogenic responses, we used EA.hy926 human vascular ECs subjected to shRNA‐mediated 3‐MST attenuation and pharmacological inhibition of proliferation, migration, and tube‐like network formation. To evaluate bioenergetic parameters, cell respiration, glycolysis, glucose uptake, and mitochondrial/glycolytic ATP production were measured. Finally, global metabolomic profiling was performed to determine the level of 669 metabolic compounds. Key Results 3‐MST‐attenuated ECs subjected to shRNA or pharmacological inhibition of 3‐MST significantly reduced EC proliferation, migration, and tube‐like network formation. 3‐MST silencing also suppressed VEGF‐induced EC migration. From bioenergetic and metabolic standpoints, 3‐MST attenuation decreased mitochondrial respiration and mitochondrial ATP production, increased glucose uptake, and perturbed the entire EC metabolome. Conclusion and Implications 3‐MST regulates bioenergetics and morphological angiogenic functions in human ECs. The data presented in the current report support the view that 3‐MST pathway may be a potential candidate for therapeutic modulation of angiogenesis. Linked Articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

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Upregulation of Cystathionine-β-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

Cited by 109 publications

References 41 publications

Identification of potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma

Identification of potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma

Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation, Migration, and Bioenergetics in Murine Colon Cancer Cells

3‐Mercaptopyruvate sulfurtransferase supports endothelial cell angiogenesis and bioenergetics

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