Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-6149
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dc.contributor.authorVaupel, Peter-
dc.contributor.authorMulthoff, Gabriele-
dc.date.accessioned2021-07-02T09:12:08Z-
dc.date.available2021-07-02T09:12:08Z-
dc.date.issued2021-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/6158-
dc.description.abstractContrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional or impaired mitochondria compensating for poor ATP yield per mole of glucose. Instead, in most tumours the Warburg effect is an essential part of a ‘selfish’ metabolic reprogramming, which results from the interplay between (normoxic/hypoxic) hypoxia-inducible factor-1 (HIF-1) overexpression, oncogene activation (cMyc, Ras), loss of function of tumour suppressors (mutant p53, mutant phosphatase and tensin homologue (PTEN), microRNAs and sirtuins with suppressor functions), activated (PI3K–Akt–mTORC1, Ras–Raf–MEK–ERK–cMyc, Jak–Stat3) or deactivated (LKB1–AMPK) signalling pathways, components of the tumour microenvironment, and HIF-1 cooperation with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include: (a) considerable acceleration of glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis and electrochemical gradients; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, non-essential amino acids, lipids and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate, which stimulates tumour growth and suppression of anti-tumour immunity – in addition, lactate can serve as an energy source for normoxic cancer cells and drives malignant progression and resistances to conventional therapies; (f) cytosolic lactate being mainly exported through upregulated lactate–proton symporters (MCT4), working together with other H+ transporters, and carbonic anhydrases (CAII, CAIX), which hydrate CO2 from oxidative metabolism to form H+ and bicarbonate; (g) these proton export mechanisms, in concert with poor vascular drainage, being responsible for extracellular acidification, driving malignant progression and resistance to conventional therapies; (h) maintenance of the cellular redox homeostasis and low reactive oxygen species (ROS) formation; and (i) HIF-1 overexpression, mutant p53 and mutant PTEN, which inhibit mitochondrial biogenesis and functions, negatively impacting cellular respiration rate. The glycolytic switch is an early event in oncogenesis and primarily supports cell survival. All in all, the Warburg effect, i.e. aerobic glycolysis in the presence of oxygen and – in principle – functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. However, as evidenced during the last two decades, in a minority of tumours primary mitochondrial defects can play a key role promoting the Warburg effect and tumour progression due to mutations in some Krebs cycle enzymes and mitochondrial ROS overproduction.en_GB
dc.language.isoengde
dc.rightsCC BY-NC*
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleRevisiting the Warburg effect : historical dogma versus current understandingen_GB
dc.typeZeitschriftenaufsatzde
dc.identifier.doihttp://doi.org/10.25358/openscience-6149-
jgu.type.dinitypearticleen_GB
jgu.type.versionPublished versionde
jgu.type.resourceTextde
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.number2700-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.journal.titleThe journal of physiologyde
jgu.journal.volume599de
jgu.journal.issue6de
jgu.pages.start1745de
jgu.pages.end1757de
jgu.publisher.year2021-
jgu.publisher.nameWiley-Blackwellde
jgu.publisher.placeHoboken, NJde
jgu.publisher.urihttps://doi.org/10.1113/JP278810de
jgu.publisher.issn1469-7793de
jgu.organisation.placeMainz-
jgu.subject.ddccode610de
jgu.publisher.doi10.1113/JP278810
jgu.organisation.rorhttps://ror.org/023b0x485
Appears in collections:JGU-Publikationen

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