Warburg Effect Signaling Pathway
Most 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, 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 the enzyme lactate dehydrogenase (LDH). In many normal cells, lactate production is typically restricted to anaerobic conditions when oxygen levels are low, however, cancer cells preferentially channel glucose towards lactate production even when oxygen is plentiful, a process termed “aerobic gycolysis” 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 can be used 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) to create nucleotides. Fatty acids are critical for new membrane production and are synthesized from citrate in the cytosol through the action of ATP-citrate lyase (ACL) to generate acetyl-CoA. This process requires NADPH reducing equivalents, which can be generated through the actions of malic enzyme, IDH1, and also from multiple steps within the PPS pathway. Serine and glycine are critical for biosynthesis of nucleic acids and lipids as well as proteins.
Several signaling pathways contribute to the Warburg Effect. 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.
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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 November 2012