Otto Warburg demonstrated the difference between metabolism in cancer ceils and that in normal adult tissue. Cancer cells take up glucose at higher rates than normal tissue but use a smaller fraction of this glucose for oxidative phosphorylation. This effect is known as aerobic glycolysis or the Warburg effect Lewis Cantley and colleagues now report that the human M2 (fetal) isoform of pyruvate kinase (PKM2), an enzyme that is involved in glycolysis, is a phosphotyrosine-binding protein and promotes the Warburg effect.
Phosphotyrosine-peptide binding is specific to the M2 isoform. PKM2 contains a 56-amino-acid stretch, which forms an allsteric pocket unique to PKM2 that allows binding of its activator, fructose-1,6-bisphosphate (FBP). Binding of phosphotyrosine peptides toPKM2 results in release of the allosteric activator FBP and subsequent inhibition of enzymatic activity.
Tyrosine phosphorylation can regulate the activity of PKM2 in cells,. Of the the different pyruvate kinase isoforms, this effect is specific to the M2 isoform and requires the phosphotyrosine-peptide binding capability.
Cancer cell lines exclusively express PKM2, and knockdown of PKM2 expression in cancer cells results in reduced glycolysis and decreased cell proliferation. Further analysis of M2KE-mutant cells revealed reduced lactate production and increased oxygen consumption compared with wild-type cells. This finding indicates that tyrosine kinase regulation of PKM2 activity is involved in mediating the Warburg effect in tumour cells.
But how do tumour cells achieve this altered metabolic phenotype? The authors reasoned that tumour tissue switches pyruvvate kinase expression from an adult isoform to the embryonic M2 isoform.
In a breast cancer tumour model PKMi is the primary- isoform before tumour development, whereas PKM2 is the primary isoform in four independent tumours.. In vivo, PKM2 expression was found to provide a selective growth advantage for tumour.
What a wonderful piece of science.
The specialised metabolism of tumour cells is critical for tumorogenesis.
Kritikou 2008, Metabolism Warburg revisited Nature Reviews cancer vol 8 p 247A
- Martin Eastwood