Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia

Metabolic reprogramming
of cancer cells is essential for tumorigenesis
in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate
kinase, plays a critical role. Herein, we describe the identification
of a nature-product-derived micheliolide (MCL) that selectively activates
PKM2 through the covalent binding at residue cysteine424 (C424), which
is not contained in PKM1. This interaction promotes more tetramer
formation, inhibits the lysine433 (K433) acetylation, and influences
the translocation of PKM2 into the nucleus. In addition, the pro-drug
dimethylaminomicheliolide (DMAMCL) with similar properties as MCL
significantly suppresses the growth of leukemia cells and tumorigenesis
in a zebrafish xenograft model. Cell-based assay with knock down PKM2
expression verifies that the effects of MCL are dependent on PKM2
expression. DMAMCL is currently in clinical trials in Australia. Our
discovery may provide a valuable pharmacological mechanism for clinical
treatment and benefit the development of new anticancer agents.