Most cancer cells get their energy through glycolysis instead of oxidative phosphorylation, even in the presence of oxygen. This process is named the Warburg effect after its discoverer, and it allows cells to proliferate even with damaged mitochondria. In 2008, researchers at Harvard Medical School discovered that one form of pyruvate kinase, PKM2, is required for the Warburg effect. The other form of pyruvate kinase is not involved. These findings make PKM2 an interesting target for developing cancer therapies.
The P13K/Akt/mTOR regulatory pathway is upstream of PKM2. The small molecule LY294002 targets P13K, so recently Lu et al. tested its effect on cancer cell proliferation.
Lu et al. grew several lines of gastric cancer cells in culture. A Western blot analysis found that PKM2 expression was increased in cancer cell lines compared to the control. They chose one cell line to study in detail. LY294002 decreased cell proliferation and increased apoptosis in this line. LY294002 also decreased the activity of lactate dehydrogenase, a biomarker of the Warburg effect.
They wanted to test whether PKM2 was part of the mechanism by which LY294002 decreased cell proliferation, so they used siRNA to knock down PKM2 on its own. siRNA-treated cells behaved similarly to LY294002-treated cells: they had lowered proliferation, increased apoptosis, and lowered lactate dehydrogenase activity. Lu et al. concluded that PKM2 is important to the mechanism of LY294002’s action.
LY294002 shows promise as an inhibitor of PKM2 and the Warburg effect.
Lu J, Chen M, Gao S, Yuan J, Zhu Z, Zou X. LY294002 inhibits the Warburg effect in gastric cancer cells by downregulating pyruvate kinase M2. 2018. Oncology letters. 15:4358-4364.