Warburg Effect Signaling Pathway
Cancer cells rely on a variety of metabolic fuels, and the specific nutrients used are impacted by both the genetic and environmental context of the cancer cell.
Most mammalian cells use glucose as a fuel source. Glucose is metabolized by glycolysis in a multistep set of reactions resulting in the creation of pyruvate. In typical cells under normal oxygen levels, much of this pyruvate enters the mitochondria where it is oxidized by the Krebs Cycle to generate ATP to meet the cell’s energy demands. However, in cancer cells or other highly proliferative cell types, much of the pyruvate from glycolysis is directed away from the mitochondria to create lactate through the action of lactate dehydrogenase (LDH/LDHA)—a process typically reserved for the low oxygen state. Lactate production in the presence of oxygen is termed “aerobic glycolysis” or the Warburg Effect.
Cancer cells frequently use glutamine as another fuel source, which enters the mitochondria and can be used to replenish Krebs Cycle intermediates or to produce more pyruvate through the action of malic enzyme. Highly proliferative cells need to produce excess lipid, nucleotide, and amino acids for the creation of new biomass. Excess glucose is diverted through the pentose phosphate shunt (PPS) and serine/glycine biosynthesis pathway to create nucleotides. Fatty acids are critical for new membrane production and are synthesized from citrate in the cytosol by ATP-citrate lyase (ACL) to generate acetyl-CoA. Acetate can also be a source of carbon for acetyl-CoA production when available. De novo lipid synthesis requires NADPH reducing equivalents, which can be generated through the actions of malic enzyme, IDH1, and also from multiple steps within the PPS pathway and serine/glycine metabolism. These reducing equivalents are also part of the defense against the increased levels of reactive oxygen species that are characteristic of cancer cells. There is also evidence that some cancer cells can scavenge extracellular protein, amino acids, and lipids. Macropinocytosis, a process that allows bulk uptake of extracellular material that can be delivered to the lysosome, is one way the cells can catabolize extracellular material and provide nutrients for cell metabolism. These nutrients can generate ATP or NADPH, or contribute directly to biomass.
Several signaling pathways contribute to the Warburg Effect and other metabolic phenotypes of cancer cells. Growth factor stimulation results in signaling through RTKs to activate PI3K/Akt and Ras. Akt promotes glucose transporter activity and stimulates glycolysis through activation of several glycolytic enzymes including hexokinase and phosphofructokinase (PFK). Akt phosphorylation of apoptotic proteins such as Bax makes cancer cells resistant to apoptosis and helps stabilize the outer mitochondrial membrane (OMM) by promoting attachment of mitochondrial hexokinase (mtHK) to the VDAC channel complex. RTK signaling to c-Myc results in transcriptional activation of numerous genes involved in glycolysis and lactate production. The p53 oncogene transactivates TP-53-induced Glycolysis and Apoptosis Regulator (TIGAR) and results in increased NADPH production by PPS. Signals impacting levels of hypoxia inducible factor (HIF) can increase expression of enzymes such as LDHA to promote lactate production, as well as pyruvate dehydrogenase kinase to inhibit the action of pyruvate dehydrogenase and limit entry of pyruvate into the Krebs Cycle. There is also increasing evidence that availability of metabolic substrates can influence gene expression by affecting epigenetic marks on histones and DNA.
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We would like to thank Prof. Matthew G. Vander Heiden, Massachusetts Institute of Technology, Cambridge, MA for reviewing this diagram.
created November 2010
revised July 2014