The Warburg effect: Evolving interpretations of an established concept

Abstract

Metabolic reprogramming and altered bioenergetics have become emerged as a hallmark of cancer and an area of active basic and translational cancer research. Drastically upregulated glucose transport and metabolism in most cancers regardless the oxygen supply, a phenomenon called the Warburg effect, is one of major focuses of the research. Warburg speculated that cancer cells, due to defective mitochondrial oxidative phosphorylation (OXPHOS), switch to glycolysis for ATP synthesis, even in the presence of oxygen. Studies in the recent decade indicated that while glycolysis is indeed drastically upregulated in almost all cancer cells, mitochondrial respiration continues to operate normally at rates proportional to oxygen supply. There is no OXPHOS-to-glycolysis switch but rather upregulation of glycolysis. Furthermore, upregulated glycolysis appears to be for synthesis of biomass and reducing equivalents in addition to ATP production. The new finding that a significant amount of glycolytic intermediates are diverted to the pentose phosphate pathway (PPP) for production of NADPH has profound implications in how cancer cells use the Warburg effect to cope with reactive oxygen species (ROS) generation and oxidative stress, opening the door for anti-cancer interventions taking advantage of this. Recent findings in the Warburg effect and its relationship with ROS and oxidative stress controls will be reviewed. Cancer treatment strategies based on these new findings will be presented and discussed.

Mitochondrial dynamics and cancer

“…This occurs by the induction of hypoxia-inducible factor 1 (HIF-1), which is considered a master regulator for the initiation and maintenance of the Warburg effect at the level of gene expression of glycolysis-related enzymes and glucose transporters. 22,23,28 HIF-1 induction can be triggered by the accumulation of ROS produced by dysfunctional mitochondria or by Krebs cycle metabolites like succinate that can inhibit HIF-1α prolyl hydroxylases in the cytosol, leading to the stabilization and activation of HIF-1α. 22,23 Succinate accumulation in mitochondria can be caused by mutations in succinate dehydrogenase, which has been documented in a familial predisposition to benign tumors.…”

“…30 MYC regulates genes involved in glucose metabolism by binding to and regulating virtually all glycolytic enzyme genes as well as numerous genes involved in mitochondrial function. 23 Deregulated MYC expression is a hallmark of a large fraction of all human tumors acting as an oncogene in approximately 30% of all human cancers. 32 Concerning mitochondria, MYC regulates the expression of over 400 mitochondrial genes, including mitochondrial transcription factor A (TFAM), an mtDNA transcription and maintenance factor, as well as PGC-1α and PGC-1β.…”

Investigation of the Low Molecular Weight Thiol Composition in a Metastatic Prostate Cancer Cell Line (LNCaP) by LC-UV-MS and NMR after Labelling with the Ellman Reagent

“…Increased glycolysis is a feature of the well-known Warburg effect of increased anaerobic respiration found in most tumour cells [22] though there have been no reports of glycerate being involved with thiol metabolism.…”

Bioenergetic adaptations in chemo-resistant ovarian cancer cells

“…Current evidence shows that OXPHOS pathways are intact in most cancer cells and the increased glycolysis is the result of an intricate interplay between oncogenes and the tumor microenvironment 36,37 . The discovery of altered cellular metabolism in cancer cells has fueled the interest in understanding the specific metabolic attributes of those cancer cells 38,39 . We characterized the bioenergetics profile of a panel of ovarian cancer cell lines and showed the existence of pronounced heterogeneity in their bioenergetics requirements with ATP-linked respiration positively correlating with spare glycolytic capacity in these cell lines.…”