Activating PKM2 to counter tumor growth

Small-molecule activators that modulate metabolism in cells can impede tumor growth, reports a study published this week in Nature Chemical Biology. These findings could be of interest for the development of cancer therapies.

Pyruvate kinase enzymes carry out the final step in glycolysis, a metabolic pathway that converts glucose into energy as well as important anabolic metabolites for cells. There are two pyruvate kinases, PKM1 and PKM2; PKM1 is the more active of the two forms of the enzyme but altered activity of PKM2 coincides with tumor cells.

Matthew Vander Heiden and colleagues report that small-molecule activators that bind specifically to PKM2 and promote the formation of the active form of the enzyme change the metabolism of tumor cells in manner that impedes tumor growth. These activators bind to a newly discovered site on PKM2, rendering the enzyme resistant to negative feedback loops that result in the production of growth-promoting metabolites. Persistent activation of PKM2 may thus cut off a tumor cell’s supply of anabolic nutrients. PKM2 activators also sensitized tumor cells to another form of stress, called oxidative stress, potentially opening the door for a new therapeutic approach: activating PKM2 in combination with promoting oxidative stress to kill tumor cells.