The Warburg effect states that cancer cells carry out glucose metabolism in a manner distinct from the glycolytic process of cells in normal tissues. Cancer cells tend to "ferment" glucose into lactate even in the presence of sufficient oxygen to support mitochondrial oxidative phosphorylation. Which of the following enzymes is most responsible for the observations accounting for the Warburg effect?

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Pyruvate kinase is responsible for converting phosphoenolpyruvate to pyruvate in glycolysis, and its altered activity in cancer cells contributes to the Warburg effect by promoting lactate production even in the presence of oxygen.  In mammals, 2 genes encode a total of 4 pyruvate kinase (PK) isoforms. The PKM gene, so called originally due to initial characterization in muscle tissues, encodes the PKM1 and PKM1 isoforms. Most tissues express either the PKM1 or PKM2. PKM1 is found in many normal differentiated tissues, whereas PKM2 is expressed in most proliferating cells, including in all cancer cell lines and tumors tested to date. PKM2 is much less active than PKM1 but is allosterically activated by the upstream glycolytic metabolite fructose 1,6-bisphosphate (FBP). PKM2 is also unique in that, unlike other PK isoforms, it can interact with phosphotyrosine in tyrosine-phosphorylated proteins such as those resulting from growth factor stimulation of cells. The interaction of PKM2 with tyrosine-phosphorylated proteins results in the release of FBP leading to reduced activity of the enzyme. Low PKM2 activity, in conjunction with increased glucose uptake, facilitates the diversion of glucose carbons into the anabolic pathways that are derived from glycolysis. So, for proliferating cells such as cancers, even though it may seem counterproductive to prevent complete oxidation of glucose solely for ATP production, the demands for carbon incorporation into biomass clearly supersedes the needs for ATP production from glucose. Of metabolic significance to proliferating cells is that they must avoid ATP production in excess of demand to avoid allosteric inhibition of PFK1. Therefore, the inhibition of PKM2 by binding to tyrosine-phosphorylated proteins, following growth factor stimulation, may serve to uncouple the ability of cells to divert the carbons from nutrients (such as glucose) into biosynthetic pathways from the production of ATP. This may, in fact, be the underlying reason why PKM2 activity has evolved to be decreased in rapidly dividing cells.

The Warburg Effect States That Cancer Cells Carry Out Glucose