Abstract
Inactivation of the M2 form of pyruvate kinase (PKM2) in cancer cells is associated with increased tumorigenicity. To test the hypothesis that tumor growth may be inhibited through the PKM2 pathway, we generated a series of small-molecule PKM2 activators. The compounds exhibited low nanomolar activity in both biochemical and cell-based PKM2 activity assays. These compounds did not affect the growth of cancer cell lines under normal conditions in vitro, but strongly inhibited the proliferation of multiple lung cancer cell lines when serine was absent from the cell culture media. In addition, PKM2 activators inhibited the growth of an aggressive lung adenocarcinoma xenograft. These findings show that PKM2 activation by small molecules influences the growth of cancer cells in vitro and in vivo, and suggest that such compounds may augment cancer therapies.
Highlights
Proliferation of cancer cells requires the accumulation of biomass—sufficient biosynthetic building blocks to replicate each nucleic acid, protein, and lipid in the cell
We screened a library of fragment-like small molecules (1,767 compounds), with molecular weights ranging from 150 to 300 Daltons, for PKM2 activators using a coupledbiochemical assay with a luminescent readout [23]
We show that activation of PKM2 with small molecules inhibited cancer cell growth in vitro and slowed tumor formation in vivo
Summary
Proliferation of cancer cells requires the accumulation of biomass—sufficient biosynthetic building blocks to replicate each nucleic acid, protein, and lipid in the cell. The need for nutrients and oxygen may exceed the capacity of poor vascularity that characterizes most tumors. Faced with such challenges, cancer cells must adjust their metabolic pathways to proliferate. Glucose provides cancer cells with the means to generate biomass through the generation of glycolytic pathway intermediates [1, 2]. FBP levels increase and PKM2 is activated, leading to high glycolytic flux. FBP levels decrease and PKM2 is inactivated, allowing glycolytic intermediates to accumulate and be diverted into biosynthetic pathways [5]
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