کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10795341 | 1052572 | 2015 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A novel effect of DMOG on cell metabolism: direct inhibition of mitochondrial function precedes HIF target gene expression
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کلمات کلیدی
PDLEPOSIRTPGC-1αAMPKHIFPHDDMOGOCRGLUT1PDKSDHBEPAS1HK2LDHAOncometaboliteesiRNAperoxisome proliferator-activated receptor γ coactivator 1αROITCSPCeGFPα-KGNF-κBAMP-activated protein kinase - AMP-پروتئین کیناز فعال شده استDMSO - DMSOROS - ROSα-ketoglutarate - α-کتوگلووتراتerythropoietin - اریتروپویتینEnergy stress - استرس انرژیinflammation - التهاب( توروم) Mitochondrial respiration - تنفس میتوکندریtumour necrosis factor α - تومور نکروز عامل αDimethyl sulfoxide - دیمتیل سولفواکسیدFIH - شاملTime-correlated single photon counting - شمارش تک فوتون وابسته به زمانHypoxia Inducible Factor - فاکتور قابل تشخیص هیپوکسیTNF-α - فاکتور نکروز توموری آلفاnuclear factor kappa-light-chain-enhancer of activated B cells - فاکتور هسته ای kappa-light-chain-enhancer از سلول های B فعال شده استfumarate hydratase - فومارات هیدراتازLactate dehydrogenase A - لاکتات دهیدروژناز Aregion of interest - منطقه مورد نظرNADH - نادانnicotinamide adenine dinucleotide reduced - نیکوتین آمید adenine dinucleotide کاهش می یابدenhanced green fluorescence protein - پروتئین فلورسانس سبز افزایش یافته استPoly-d-lysine - پلی دی لیزینPyruvate dehydrogenase kinase - پیرووات دهیدروژناز کینازglucose transporter 1 - گلوکز 1Reactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم کشاورزی و بیولوژیک
دانش گیاه شناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Abnormal accumulation of oncometabolite fumarate and succinate is associated with inhibition of mitochondrial function and carcinogenesis. By competing with α-ketoglutarate, oncometabolites also activate hypoxia inducible factors (HIFs), which makes oncometabolite mimetics broadly utilised in hypoxia research. We found that dimethyloxalylglycine (DMOG), a synthetic analogue of α-ketoglutarate, commonly used to induce HIF signalling, inhibits O2 consumption in cancer cell lines HCT116 and PC12, well before activation of HIF pathways. A rapid suppression of cellular respiration was accompanied by a decrease in histone H4 lysine 16 acetylation and not abolished by double knockdown of HIF-1α and HIF-2α. In agreement with this, production of NADH and state 3 respiration in isolated mitochondria were down-regulated by the de-esterified DMOG derivative, N-oxalylglycine. Exploring the roles of DMOG as a putative inhibitor of glutamine/α-ketoglutarate metabolic axis, we found that the observed suppression of OxPhos and compensatory activation of glycolytic ATP flux make cancer cells vulnerable to combined treatment with DMOG and inhibitors of glycolysis. On the other hand, DMOG treatment impairs deep cell deoxygenation in 3D tissue culture models, demonstrating a potential to relieve functional stress imposed by deep hypoxia on tumour, ischemic or inflamed tissues. Indeed, using a murine model of colitis, we found that O2 availability in the inflamed colon tissue rapidly increased after application of DMOG, which could contribute to the known therapeutic effect of this compound. Overall, our results provide new insights into the relationship between mitochondrial function, O2 availability, metabolic reprogramming and associated diseases.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Bioenergetics - Volume 1847, Issue 10, October 2015, Pages 1254-1266
Journal: Biochimica et Biophysica Acta (BBA) - Bioenergetics - Volume 1847, Issue 10, October 2015, Pages 1254-1266
نویسندگان
Alexander V. Zhdanov, Irina A. Okkelman, Fergus W.J. Collins, Silvia Melgar, Dmitri B. Papkovsky,