Small-molecule pyruvate kinase enzyme (PKM2) activator drugs may help to prevent tumour growth, according to research published in the journal Science.
By keeping PKM2 activity at lower-than-normal levels, cancer cells are able to withstand damage caused by oxidative stress and the generation of potentially toxic reactive oxygen species (ROS).
“Growth factor signalling emerged relatively late in evolution but glycolysis is a highly conserved process and occurs in bacteria much like it occurs in human cells,” said lead author Dimitrios Anastasiou.
“We were intrigued by the possibility that something other than growth factors might also be influencing the activity of PKM2.
“To survive, cancer cells require the ability to squelch potentially toxic ROS molecules, which can arise as a result of both their aberrant metabolism as well as their environment.
“We thought that PKM2 might somehow be playing a supporting role in tamping down ROS.”
To test this hypothesis, the scientific team embarked on a series of experiments that showed ROS can inhibit PKM2 activity, and that low PKM2 activity under oxidative stress helps push glucose into pathways that generate antioxidant molecules.
“We engineered cells to express a PKM2 mutant that is resistant to ROS-induced inhibition,” said Anastasiou.
“This showed us that, when challenged by oxidative stress, these cells died more readily than cells expressing the wild-type oxidizable version of PKM2.
“Strikingly, we also observed that oxidation-resistant PKM2 could not efficiently support the ability of human lung-cancer cells to form tumours in mice, but that this defect could be rescued by treating mice with an antioxidant in their water.”