The Warburg effect: evolving interpretations of an established concept

Abstract

Metabolic reprogramming and altered bioenergetics have emerged as hallmarks of cancer and an area of active basic and translational cancer research. Drastically upregulated glucose transport and metabolism in most cancers regardless of the oxygen supply, a phenomenon called the Warburg effect, is a 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 is 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 anticancer 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.

Keywords: Glucose transport; HIF; MYC; Metabolism reprogram; ROS; Warburg effect.

Figure 1. The Warburg effect with its extended functions and regulations

Relative amount of glucose consumption and its metabolic products in normal (blue box) and cancer (orange box) under normoxic condition are shown and compared. Red ↑ indicates an elevated level in cancer cells. The enzymes in green function in both normal and cancer cells; and the enzyme in orange functions mainly in cancer cells.

Figure 2. Potential drug targets in ATP-sharing model

According to this model, a symbiotic relationship exists among cancer and stromal cells in a tumor. Normoxic cancer cells and stromal cells recruited by hypoxic cancer cells release ATP into intratumoral space, leading to a large intratumoral ATP concentration increase. Highly concentrated intraturmoral ATP is then internalized by hypoxic cancer cells through macropinocytosis and/or other endocytic processes, supplementing the intracellular ATP pool in hypoxic cancer cells. Meanwhile, cancer cells uptake and release of lactate through transporters MCT1 and MCT4. Potential targets for anticancer therapeutic intervention in this model are shown by symbol .