The Warburg Effect: Historical Dogma Versus Current Rationale.

Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary and permanent consequence of dysfunctional mitochondria compensating for a poor ATP yield per mole glucose. Instead, the Warburg effect is an essential part of a "selfish" metabolic reprogramming, which results from the interplay between (normoxic or hypoxic) HIF-1 overexpression, oncogene activation (cMyc, Ras), loss of function of tumor suppressors (mutant p53, mutant PTEN, microRNAs and sirtuins with suppressor functions), activated (PI3K/Akt/mTORC1, Ras/Raf/Mek/Erk/c-Myc) or deactivated (AMPK) signaling pathways, components of the tumor microenvironment, and HIF-1 cooperations with epigenetic mechanisms. Molecular and functional processes of the Warburg effect include (a) considerably accelerated glycolytic fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis; (c) backup and diversion of glycolytic intermediates facilitating the biosynthesis of nucleotides, nonessential amino acids, lipids, and hexosamines; (d) inhibition of pyruvate entry into mitochondria; (e) excessive formation and accumulation of lactate which stimulates tumor growth and suppression of antitumor immunity (in addition, lactate can serve as an energy source for normoxic cancer cells, contributes to extracellular acidosis, and thus drives malignant progression and resistances to conventional therapies); (f) maintenance of the cellular redox homeostasis and low ROS formation; and (g) HIF-1 overexpression, mutant p53, and mutant PTEN which inhibit mitochondrial biogenesis and functions, thus 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 - finally - poor patient outcome.