Understanding the Warburg effect: the metabolic requirements of cell proliferation

Abstract

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

Fig. 1

Microbes and cells from multicellular organisms have similar metabolic phenotypes under similar environmental conditions. Unicellular organisms undergoing exponential growth often grow by fermentation of glucose into a small organic molecule such as ethanol. These organisms, and proliferating cells in a multicellular organism, both metabolize glucose primarily through glycolysis, excreting large amounts of carbon in the form of ethanol, lactate, or another organic acid such as acetate or butyrate. Unicellular organisms starved of nutrients rely primarily on oxidative metabolism, as do cells in a multicellular organism that are not stimulated to proliferate. This evolutionary conservation suggests that there is an advantage to oxidative metabolism during nutrient limitation and nonoxidative metabolism during cell proliferation.

Fig. 2

Schematic representation of the differences between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (Warburg effect). In the presence of oxygen, nonproliferating (differentiated) tissues first metabolize glucose to pyruvate via glycolysis and then completely oxidize most of that pyruvate in the mitochondria to CO₂ during the process of oxidative phosphorylation. Because oxygen is required as the final electron acceptor to completely oxidize the glucose, oxygen is essential for this process. When oxygen is limiting, cells can redirect the pyruvate generated by glycolysis away from mitochondrial oxidative phosphorylation by generating lactate (anaerobic glycolysis). This generation of lactate during anaerobic glycolysis allows glycolysis to continue (by cycling NADH back to NAD⁺), but results in minimal ATP production when compared with oxidative phosphorylation. Warburg observed that cancer cells tend to convert most glucose to lactate regardless of whether oxygen is present (aerobic glycolysis). This property is shared by normal proliferative tissues. Mitochondria remain functional and some oxidative phosphorylation continues in both cancer cells and normal proliferating cells. Nevertheless, aerobic glycolysis is less efficient than oxidative phosphorylation for generating ATP. In proliferating cells, ~10% of the glucose is diverted into biosynthetic pathways upstream of pyruvate production.

Fig. 3

Metabolic pathways active in proliferating cells are directly controlled by signaling pathways involving known oncogenes and tumor suppressor genes. This schematic shows our current understanding of how glycolysis, oxidative phosphorylation, the pentose phosphate pathway, and glutamine metabolism are interconnected in proliferating cells. This metabolic wiring allows for both NADPH production and acetyl-CoA flux to the cytosol for lipid synthesis. Key steps in these metabolic pathways can be influenced by signaling pathways known to be important for cell proliferation. Activation of growth factor receptors leads to both tyrosine kinase signaling and PI3K activation. Via AKT, PI3K activation stimulates glucose uptake and flux through the early part of glycolysis. Tyrosine kinase signaling negatively regulates flux through the late steps of glycolysis, making glycolytic intermediates available for macromolecular synthesis as well as supporting NADPH production. Myc drives glutamine metabolism, which also supports NADPH production. LKB1/AMPK signaling and p53 decrease metabolic flux through glycolysis in response to cell stress. Decreased glycolytic flux in response to LKB/AMPK or p53 may be an adaptive response to shut off proliferative metabolism during periods of low energy availability or oxidative stress. Tumor suppressors are shown in red, and oncogenes are in green. Key metabolic pathways are labeled in purple with white boxes, and the enzymes controlling critical steps in these pathways are shown in blue. Some of these enzymes are candidates as novel therapeutic targets in cancer. Malic enzyme refers to NADP⁺-specific malate dehydrogenase [systematic name (S)-malate:NADP⁺ oxidoreductase (oxaloacetate-decarboxylating)].

Fig. 4

Decreased metabolism of glucose by tumors, visualized by PET with the glucose analog FDG, predicts response to anticancer therapy. Shown are fused coronal images of FDG-PET and computerized tomography (CT) obtained on a hybrid PET/CT scanner after the infusion of FDG in a patient with a form of malignant sarcoma (gastrointestinal stromal tumor) before and after therapy with a tyrosine kinase inhibitor (sunitinib). The tumor (T) is readily visualized by FDG-PET/CT before therapy (left). After 4 weeks of therapy (right), the tumor shows no uptake of FDG despite persistent abnormalities on CT. Excess FDG is excreted in the urine, and therefore the kidneys (K) and bladder (B) are also visualized as labeled. [Image courtesy of A. D. Van den Abbeele, Dana-Farber Cancer Institute, Boston]