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Different from normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance through aerobic glycolysis. The common feature of this altered metabolism is increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and together is known as the Warburg Effect.
The Warburg Effect has been documented for over 90 years. In the 1920s, Otto Warburg and colleagues observed that tumors were taking up enormous amounts of glucose compared to what was seen in the surrounding tissue. With extensively studied, this metabolism of glucose was then termed the Warburg Effect in the early 1970s, which is required for tumor growth. In tumors and other proliferating or developing cells, the rate of glucose uptake dramatically increases and lactate is produced, even in the presence of oxygen and fully functioning mitochondria. That means in order to kill tumor cells by depriving them of energy, both glucose and oxygen had to be eliminated.
Figure 1.An overview of Warburg Effect
The Warburg Effect confers direct signaling functions on tumor cells. Glucose can be transported into plasma by glucose transporter and phosphorylated to glucose-6-phosphate (G6P) by hexokinase which is regulated by c-Myc and Akt. G6P converts to fructose-6-phosphate (F6P) which is further phosphorylated to fructose-1, 6-bisphosphate (FBP) under the phosphorfructo-kinase (PFK) for glycolysis. The products of FBP cleavage are glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP), and the phosphoenolpyruvate (PEP) was initially reported to partially inhibit FBP activity at high concentrations.
G6P can be also used for nucleotide synthesis through the NADP+/NADPH-dependent way and enzyme glucose-6-phosphate dehydrogenase (G6PDH), with the production of 6-P-gluconolactone, 6-P-gluconate, and ribose-5-phosphate.
This metabolic wiring allows for both NADPH production and acetyl-CoA flux to the cytosol for lipid synthesis. 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. The c-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 LKB1/AMPK or p53 may be an adaptive response to shut off proliferative metabolism during periods of low energy availability or oxidative stress.
Growth factor signaling also regulates the activity of the pyruvate kinase M2 (PKM2) by tyrosine kinase and modulates flux of carbon through the later steps of glycolysis. This modulation of pyruvate kinase may facilitate the redirection of glucose metabolites into the pentose phosphate shunt, as well as nucleotide and amino acid biosynthesis pathways. The conversion of both glucose and glutamine to lactate involves the enzyme lactate dehydrogenase A.
Glutamine uptake by mitochondria is critical for lipid synthesis in that it supplies carbon in the form of mitochondrial oxaloacetate to maintain citrate production in the first step of the tricarboxylic acid cycle (TCA cycle). The mitochondria are key components of the biosynthetic program whose substrates in the TCA cycle (such as malate, oxaloacetate, citrate, α-Ketoglutarate, and succinate) are used for nucleotide, amino acid, and lipid biosynthesis.
The Warburg Effect presents an advantage for cell growth in a multicellular environment. Acidification of the microenvironment and other metabolic crosstalk are intriguing possibilities. Elevated glucose metabolism decreases the pH in the microenvironment due to lactate secretion. The potential benefits of acidosis to cancer cells are multifold. The availability of glucose appears to be a result of direct competition between tumor and tumor infiltrating lymphocytes (TIL). The high rates of glycolysis limit the availability of glucose for TILs that require sufficient glucose for their effector functions. Supporting this proposal is direct evidence indicating that targeting aerobic glycolysis in the tumor has the added benefit of increasing the supply of glucose to TILs and thus boosting their main function, which is to eradicate the tumor cells.
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