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.
Herein we detail the discovery of a series of parthenolide dimers as activators of PKM2 and evaluation of their anti-GBM activities. The most promising compound 5 showed high potency to activate PKM2 with an AC 50 value of 15 nM, inhibited proliferation and metastasis, and induced apoptosis of GBM cells. Compound 5 could promote tetramer formation of PKM2 and reduce nucleus translocation of PKM2 in GBM cells without influence on the expression of total PKM2, thereby inhibiting the STAT3 signal pathway in vitro and in vivo. PKM2 knockdown assay demonstrated that the anti-GBM effect of 5 mainly depended on the expression of PKM2 in vitro and in vivo. Compound 16, a prodrug of 5, markedly suppressed U118 tumor xenograft growth and reduced the weight of tumor. On the basis of these investigations, we propose that 16 might be considered as a promising lead compound for discovery of anti-GBM drugs.
Glioblastoma (GBM) is the most prevalent malignant tumor in the central nervous system. Aerobic glycolysis, featured with elevated glucose consumption and lactate production, confers selective advantages on GBM by utilizing nutrients to support rapid cell proliferation and tumor growth. Pyruvate kinase 2 (PKM2), the last rate-limiting enzyme of glycolysis, is known to regulate aerobic glycolysis, and considered as a novel cancer therapeutic target. Herein, we aim to describe the cellular functions and mechanisms of a small molecular compound dimethylaminomicheliolide (DMAMCL), which has been used in clinical trials for recurrent GBM in Australia. Our results demonstrate that DMAMCL is effective on the inhibition of GBM cell proliferation and colony formation. MCL, the active metabolic form of DMAMCL, selectively binding to monomeric PKM2 and promoting its tetramerization, was also found to improve the pyruvate kinase activity of PKM2 in GBM cells. In addition, non-targeting metabolomics analysis reveals multiple metabolites involved in glycolysis, including lactate and glucose-6-phosphate, are decreased with DMAMCL treatment. The inhibitory effects of DMAMCL are observed to decrease in GBM cells upon PKM2 depletion, further confirming the importance of PKM2 in DMAMCL sensitivity. In conclusion, the activation of PKM2 by DMAMCL results in the rewiring aerobic glycolysis, which consequently suppresses the proliferation of GBM cells. Hence, DMAMCL represents a potential PKM2-targeted therapeutic agent against GBM.
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