Revisiting the Warburg effect: historical dogma versus current understanding

Abstract

Contrary 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.

Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

“…This is a remarkable characteristic of cancer cells and has recently been applied as a method of detecting cancer by exploiting the characteristic of excessive glucose utilization by cancer cells [5]. It is essential to consider that cancer cells complete the glycolysis process regardless of absence or presence of oxygen [6]. When cancer cells only obtain glycolysis-dependent energy even in the presence of oxygen, the effect is called the "Warburg effect" [7].…”

Implications of Standardized Uptake Values of Oral Squamous Cell Carcinoma in PET-CT on Prognosis, Tumor Characteristics and Mitochondrial DNA Heteroplasmy

“…Since then, research has shown that tumor metabolism is not a static function but rather an essential part of metabolic reprogramming based on necessary adaptations caused by external or internal cellular factors [ 57 ]. It has been shown for example that the interplay between hypoxia-inducible factor-1 (HIF-1) overexpression, HIF-1 cooperation with epigenetic mechanisms, oncogene activation (cMyc, Ras), loss of function of tumor suppressors (mutant p53, mutant PTEN, miRNAs and sirtuins with suppressor functions), activated (PI3K-Akt-mTORC1, Ras-Raf-MEK-ERK-cMyc, Jak-Stat3) or deactivated (LKB1-AMPK) signaling pathways, and components of the tumor microenvironment (such as cancer-associated-fibroblasts) are likely to influence the metabolic phenotype of a tumor cell [ 11 ]. To see if the metabolic reprogramming of OSCC cells leading to increased SUVmax value might be linked to dysfunctions in ETS proteins, we evaluated if mutations in mtDNA coding for ETS genes at a certain level of heteroplasmy could have effects on SUVmax values by alterations in energy metabolism.…”

“…According to the original Warburg model, complex cellular processes including mutations in genes coding for ETS proteins lead to this metabolic switch [ 10 ]. Recent work has extended this model, indicating that not only ETS mutations but also an interplay between various cellular signaling processes and interaction with the tumor microenvironment can lead to this metabolic phenotype [ 11 ]. However, metabolic analyses of various tumor models suggest that a fully functional ETS is a prerequisite for the malignant behavior of many cancer types [ 12 ].…”

Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

“…Glycolytic phenotype is an important part of the metabolic reprogramming of cancer cells and occurs at an early stage of oncogenesis, i.e., before the development of tissue hypoxia. The history and current knowledge of the mechanisms and consequences of the Warburg effect are presented in a recent excellent review [ 45 ]. On the other hand, the role of Insulin/IGF signaling in the acquisition of the Warburg metabolic phenotypes in colorectal cancer cells is still not fully described [ 33 ].…”